Thérapie cellulaire dendritique

C'est quoi?

Cette information a été composée par le Fonds Anticancer et est basée sur l'information professionnelle. Cette information a été mise à jour en avril 2013.  Ce résumé est actuellement en train d’être mis à jour. Pour plus d’information ou des question, veuillez contacter info@anticancerfund [dot] org.
 

Les cellules dendritiques (CD) sont un type de globules blancs qui fait partie du système immunitaire de notre corps. Ces cellules ont la capacité très développée d'activer le système immunitaire.

  • Mécanisme d’action

Les cellules dendritiques utilisées pour la thérapie par cellules dendritiques (appelée également vaccination par CD) sont manipulées en laboratoire pour renforcer leur capacité à activer le propre système immunitaire du patient afin d’attaquer les cellules cancéreuses de manière spécifique. Une fois réadministrées aux patients, on pense que ces cellules dendritiques manipulées sont en mesure d'éradiquer les cellules cancéreuses et de provoquer le rétrécissement ou la disparition de la tumeur.

  • Source des cellules dendritiques

Les CD utilisées pour la thérapie par cellules dendritiques proviennent des propres globules blancs du patient. On peut les obtenir directement par prélèvement sanguin sur le patient ou en les recréant en laboratoire à partir de précurseurs de cellules dendritiques.

  • Protocole de traitement

Étant donné que la plupart des traitements anticancéreux par cellules dendritiques sont encore à une phase expérimentale, plusieurs protocoles de vaccination actuellement sont utilisés. Les cellules dendritiques sont habituellement injectées dans un vaisseau sanguin ou dans la peau. Parfois, elles sont également injectées dans un ganglion lymphatique ou directement dans la tumeur cancéreuse. La durée du traitement dépend principalement de la réponse du patient à cette thérapie. Les vaccinations peuvent être administrées à un rythme hebdomadaire, bimensuel au mensuel.

  • Coûts du traitement

La plupart des patients traités par cellules dendritiques participent en fait à des essais cliniques, car pour la majorité des cancers (à l'exception du cancer de la prostate), ce type de traitement est encore dans une phase expérimentale.
À ce jour, il n'existe qu'un seul agrément officiel accordé par le Secrétariat américain aux produits alimentaires et pharmaceutiques en 2010, précisément pour l'utilisation de la thérapie par cellules dendritiques dans le traitement du cancer de la prostate. Ce vaccin par cellules dendritiques est commercialisé sous la marque Provenge® et coûte approximativement 93 000 $ pour un cycle complet de vaccination.

Efficace?

Plus de 200 études cliniques portant sur le traitement du cancer par cellules dendritiques ont été réalisées chez l'homme. Les résultats de ces études ont montré notamment que la thérapie par cellules dendritiques pouvait prolonger la vie du patient, et pour certains d'entre eux, pouvait même conduire à une guérison complète.

La thérapie par CD est plus efficace dans les cancers au stade précoce ou au stade dans lequel le patient ne présente plus les symptômes de la maladie, mais peut toujours conserver un petit nombre de cellules cancéreuses résiduelles. Du fait que tous les patients ne répondent pas positivement de manière similaire à la thérapie par cellules dendritiques, cette dernière sera probablement associée à de la chimiothérapie ou à d'autres modalités de traitement anticancéreux pour améliorer les chances du patient de guérir complètement.

Les patients qui participeront à de futurs essais cliniques recevront des cellules dendritiques dont on aura amélioré la capacité à activer leur propre système immunitaire pour attaquer spécifiquement les cellules cancéreuses. Ces patients bénéficieront également du protocole de traitement le plus approprié pour leur type de cancer, en termes de site d’injection ou de thérapie associée aux traitements classiques du cancer.

  • Mélanome

Le mélanome est un type de cancer dans lequel la vaccination par cellules dendritiques a été étudiée de manière exhaustive dans 54 essais cliniques enrôlant 967 patients. Les CD y étaient injectées dans la peau, dans un ganglion lymphatique, un vaisseau lymphatique ou un vaisseau sanguin. Plus le stade du cancer était précoce, plus la croissance du cancer s'est avérée susceptible de s'arrêter après la vaccination par cellules dendritiques. Chez approximativement un patient vacciné sur trois, le cancer n'a pas empiré et chez environ 9 % des patients traités par CD, la masse tumorale avait diminué ou même disparu. L'essai clinique contrôlé le plus important a démontré que les patients vaccinés par cellules dendritiques vivaient en moyenne 9,7 mois plus longtemps que les patients recevant une chimiothérapie.

  • Cancer de la prostate

Le cancer de la prostate est un autre type de cancer dans lequel la vaccination par cellules dendritiques a été étudiée de manière exhaustive dans 17 essais cliniques enrôlant 720 patients. Le mode d'administration des cellules dendritiques le plus bénéfique contre le cancer de la prostate semble être l'injection dans la peau, dans un ganglion lymphatique ou dans un vaisseau lymphatique (ou une combinaison de ces modes d'administration), plutôt que dans un vaisseau sanguin. La thérapie par cellules dendritiques a montré des résultats bénéfiques chez la moitié des patients vaccinés. Une réduction partielle ou complète du cancer a été montrée chez environ 8 % d’entre eux. Chez la plupart des patients ayant bénéficié du traitement par cellules dendritiques, le développement du cancer a été arrêté, ce qui a généré de bons taux de survie. Les malades vaccinés par cellules dendritiques ont vécu en moyenne quatre mois de plus que ceux n'ayant pas reçu cette thérapie.

Dans le cas du carcinome rénal, il a été réalisé 12 essais cliniques à petite échelle sur la thérapie par cellules dendritiques enrôlant un total de 186 patients. Tous les patients présentaient des métastases et avait été traités par des thérapies classiques avant la thérapie par cellules dendritiques. La vaccination par CD a été administrée dans un ganglion lymphatique ou dans la peau. On a observé un arrêt de l'aggravation du cancer chez environ la moitié des patients vaccinés par cellules dendritiques. Chez presque 13 % des personnes traitées par cellules dendritiques, la masse cancéreuse a diminué ou disparu.

  • Cancer du cerveau

La plupart des patients atteints d'un cancer du cerveau et participant aux 22 essais cliniques à petite échelle en cours souffrent d'un glioblastome multiforme ou d'un astrocytome anaplasique, deux types de cancer du cerveau désignés sous le nom de gliome. Les résultats actuels de ces études indiquent que les patients souffrant d'un cancer du cerveau peuvent augmenter leur longévité de l’ordre de 7 à 25 mois si la thérapie par cellules dendritiques est intégrée dans leur schéma thérapeutique global de chirurgie, radiothérapie et chimiothérapie. Lorsqu'ils sont traités par cellules dendritiques, la majorité des patients nouvellement diagnostiqués peuvent présenter une probabilité de survie d'au moins un an.

  • Cancers hématologiques

Leucémie

La thérapie par cellules dendritiques est considérée comme une option valable pour réduire le risque de rechute chez les patients ayant déjà été traités pour une leucémie. Après tout, la persistance d'un très petit nombre de cellules résiduelles de la leucémie constitue un problème majeur à la fois dans la leucémie myéloïde aiguë (LMA) et la leucémie myéloïde chronique (CML). À terme, ces cellules résiduelles peuvent former un nouveau cancer. Des essais cliniques à petite échelle sur la vaccination par cellules dendritiques ont conduit à des résultats plutôt mitigés, où la rémission a été stabilisée seulement chez un faible nombre de personnes. Chez certains patients, on a pu constater une réponse immunitaire contre les cellules cancéreuses, et celle-ci n'était pas assez forte pour détruire les cellules leucémiques. Différentes associations thérapeutiques intégrant la vaccination par cellules dendritiques feront l'objet de futures études.

Le myélome multiple

La thérapie par cellules dendritiques vise à détruire toutes les cellules cancéreuses restantes après une première chimiothérapie et la transplantation de cellules souches. Les essais cliniques portant sur la vaccination par cellules dendritiques dans le myélome multiple ne comptent toutefois que 7 essais à petite échelle enrôlant un total de 94 patients. Le vaccin à cellules dendritiques a été injecté sous la peau ou dans un vaisseau sanguin. Ces études ont rapporté un bénéfice en termes de la destruction des cellules cancéreuses résiduelles chez certains patients et de la survie de près de deux ans, avec des durées s'étalant de six mois à cinq ans sans aucune aggravation de la maladie. Pourtant, ces résultats doivent être confirmés par d'autres essais enrôlant un nombre plus important de participants.

Lymphome

Dans le cas du lymphome folliculaire à cellules B, deux essais cliniques à petite échelle ont été menés sur la thérapie par cellules dendritiques chez un total de 39 patients ayant préalablement reçu des traitements classiques. Le vaccin à cellules dendritiques a été administré dans un vaisseau sanguin. Chez 70 % des patients, le cancer ne s'est pas aggravé sur une durée moyenne de 41 mois après la vaccination. Chez 22 % des patients, la vaccination par cellules dendritiques a même détruit certaines cellules cancéreuses. Des patients souffrant d’un lymphome cutané à cellules T et d’un lymphome à cellules B indolent ont été traités par cellules dendritiques dans deux essais cliniques séparés à petite échelle. Certains patients, quoiqu'il s'agisse d'une minorité d'entre eux, ont été guéris et chez la moitié des participants, le cancer ne s'est pas aggravé après la vaccination par CD.

  • Cancer du sein

Dans le cas du cancer du sein, 7 essais cliniques à petite échelle ont été menés sur la thérapie par cellules dendritiques enrôlant un total de 115 patientes. Les participantes souffraient d'un cancer du sein métastatique ou d'un carcinome canalaire in situ, un cancer du sein non invasif qui débute à l'intérieur des canaux galactophores. Chez près de la moitié de ces dernières patientes, la vaccination par CD a provoqué une réduction du cancer. Chez près d'un tiers des patientes atteintes de la maladie métastatique, le cancer a cessé de croître grâce à la vaccination par CD. Une patiente a même été presque guérie, en ne présentant que quelques traces résiduelles de la tumeur. Aujourd'hui, les chercheurs travaillent sur un test de dépistage en mesure de sélectionner les patientes atteintes d'un cancer du sein et chez qui la thérapie par cellules dendritiques serait bénéfique.

quinze essais cliniques à petite échelle ont été réalisés  chez un total de 141 patients atteints d’un cancer colorectal. La majorité de ces participants présentaient un cancer colorectal avancé avec des métastases. Les réponses à la thérapie par cellules dendritiques ont varié considérablement : certains patients ont observé une inhibition de la croissance de leur cancer, alors que d'autres n'ont constaté aucun bénéfice du tout.

  • Cancer du foie

Dans le cas du cancer du foie, 4 essais cliniques à petite échelle ont été réalisés sur la thérapie par cellules dendritiques enrôlant un total de 90 patients. Le vaccin à CD était injecté dans un ganglion lymphatique ou un vaisseau sanguin, ou directement dans la tumeur cancéreuse. Lors de ces essais, on a comparé deux groupes de patients présentant un stade avancé de cancer du foie. Un premier groupe recevait un traitement classique, tandis qu'un second recevait une thérapie par cellules dendritiques en plus d’un traitement classique. Les résultats ont montré que les patients vaccinés par CD avaient cinq fois plus de chances de présenter une survie plus longue d'au moins une année comparé aux patients recevant uniquement le traitement classique.

 

  • Cancer du poumon

Trois essais cliniques à petite échelle ont été réalisés sur la thérapie à cellules dendritiques chez un total de 23 patients souffrant du cancer du poumon. Les réponses à la thérapie par cellules dendritiques ont varié considérablement : certains patients ont gagné un avantage en termes de survie presque deux fois plus important que la moyenne attendue, d'autres patients n'ont pas vu leur cancer s'aggraver alors que d’autres n'ont pas répondu du tout au traitement.

  • Autres cancers

Des essais cliniques à petite échelle et indépendants ont déjà montré que la thérapie à cellules dendritiques est également envisageable pour le traitement de plusieurs types de cancer tel que le cancer de la thyroïde, de l'ovaire, du col de l'utérus, de l'utérus, les cancers gastro-intestinaux, du pancréas et du cartilage. L'amélioration des protocoles de traitement pour ces types de cancer est en cours.

 

Sans danger?

La thérapie par cellules dendritiques est généralement bien tolérée et considérée comme un traitement sûr. Les effets secondaires possibles, le cas échéant, sont généralement bénins.

  • Effets indésirables les plus fréquents

Les effets secondaires légers qui peuvent se produire un ou deux jours après l'administration du vaccin incluent notamment des frissons, de la fièvre, de l'asthénie, des maux de tête, des tremblements, de la dyspnée et des vomissements. Certains patients signalent également des réactions locales sur le site d'injection.

  • Effets indésirables moins fréquents

Parfois, des douleurs musculaires, osseuses ou articulaires peuvent survenir. Une minorité de personnes peut également souffrir de fatigue.

  • Effets indésirables rares

De manière sporadique, on peut noter des phénomènes auto-immuns, par exemple, une disparition de la pigmentation de la peau dans certaines zones. Toutefois, un certain degré d'auto-immunité est considéré comme bénéfique pour l'efficacité thérapeutique, car cela démontre une bonne activation du système immunitaire du patient.

 

Plus d'info

La thérapie cellulaire dendritique est une nouvelle approche immunothérapeutique basée sur une thérapie cellulaire autologue. Il s’agit d’un traitement personnalisé qui a récemment été appliqué à différents cancers comme le mélanome, le glioblastome et le cancer de la prostate. Dans la plupart des cancers, la thérapie est expérimentale et les protocoles par type de cancer sont très différents. Le défi principal est de démontrer des réponses durables ou une amélioration de la survie corrélée à la réponse immunitaire. Lors d’une table ronde organisée par le Fonds Anticancer à Bruxelles le 2 et 3 septembre 2010, les experts académiques du monde entier se sont rassemblés pour discuter du statut, du choix d’un protocole et de l’avenir de cette thérapie prometteuse mais qui requiert un travail important.

 

COMMUNIQUE DE PRESSE - Septembre 2010

Le Fonds Anticancer:
Table ronde sur la thérapie cellulaire dendritique en oncologie

Bruxelles, le 14 septembre - Les 2 et 3 septembre, le Fonds Anticancer a animé une table ronde à Bruxelles à laquelle ont été conviés de grands spécialistes de la thérapie cellulaire dendritique appliquée à l'oncologie. La thérapie cellulaire dendritique consiste à isoler les globules blancs du patient, à les transformer au laboratoire, puis à les réadministrer au patient afin d’obtenir une réponse immunitaire plus importante. L'objectif de cette table ronde était de faire le point sur la thérapie cellulaire dendritique dans la lutte contre le cancer afin d'être en mesure de fournir des informations précises au sujet de cette approche thérapeutique actuellement disponible dans des situations très diverses, allant du traitement dans des hôpitaux universitaires dans le cadre d’essais cliniques au traitement dans des établissements douteux. 

En général, tous les spécialistes s'accordent pour dire que les cellules dendritiques devraient être combinées avec d'autres traitements, que ce soit dans le cadre d'une approche immunologique, ciblée ou conventionnelle. Il existe de nombreuses raisons d'associer une thérapie cellulaire dendritique avec une chimiothérapie, laquelle pourrait alors être administrée à plus faible dose, car la chimiothérapie pourrait accroître la sensibilité de la tumeur à la mort cellulaire provoquée par le système immunitaire. Par conséquent, les spécialistes recommandent dans la mesure du possible l'association d'une thérapie cellulaire dendritique avec le protocole de soins standard pour chaque type de cancer.

Malheureusement, le développement clinique de la thérapie cellulaire autologue, qui implique plusieurs essais cliniques pour sélectionner les combinaisons et les protocoles optimaux, est retardé par le manque d'intérêt de la part de l'industrie pharmaceutique. En conclusion, la thérapie cellulaire dendritique présente un potentiel, mais n'en est qu'à ses balbutiements, et a besoin d'un soutien suffisant pour assurer son développement clinique de façon optimale.Globalement, tous les spécialistes affirment que la thérapie cellulaire dendritique constitue une approche sûre sans effets secondaires majeurs. De légères réactions auto-immunes ont parfois été observées, mais ces effets sont considérés comme une indication de l'efficacité thérapeutique du traitement. Dans les travaux présentés, il a été démontré que la thérapie cellulaire dendritique pouvait prolonger la vie des patients voire, parfois, entraîner une « guérison » complète. Il est par conséquent nécessaire d'approfondir l’analyse des paramètres influant sur l'évolution de la maladie chez ces patients « guéris » pour améliorer la thérapie cellulaire dendritique et identifier le type de patients les plus susceptibles de bénéficier de cette thérapie. Plusieurs améliorations peuvent encore être apportées pour renforcer l'efficacité de cette thérapie, à savoir déterminer le moment et la fréquence d'administration des injections, mieux cibler la population cible et maximiser le potentiel des cellules dendritiques. 

Résumé

This text was written by Sofie Noppe and has been reviewed by Dr. An Van Nuffel, Dr. Brenda De Keersmaecker and Daphné Benteyn. Last updated: April 2013.  This summary is currently being updated. For more information or questions please contact info@anticancerfund [dot] org.

 

Dendritic cell vaccination (DC vaccination) is a personalized active immunotherapy. With the help of dendritic cells (DCs) a cancer patient’s immune system is manipulated in order to stimulate anti-tumour immunity and to bypass tumour-induced immunosuppression. It is claimed and rationalized that DC-induced activation of the patient’s own immune system could result in eradication of tumour cells and shrinkage or clearance of the tumour.
More than 200 clinical trials have been performed using DCs as adjuvants in cancer therapy (melanoma, prostate cancer, renal cell carcinoma, brain tumours, haematological cancers, breast cancer, colorectal cancer, liver cancer, lung cancer and thyroid cancer amongst others). A majority of the trials are phase I or phase I/II clinical trials in which clinical efficacy is difficult to assess. Limited phase III trials were conducted to date in prostate cancer and melanoma. Nevertheless some overall promising results have been obtained for DC vaccination in the maintenance of stable disease, referring to a survival benefit. Complete remissions or partial remissions are observed in a minority of patients. Survival benefits demonstrated in the phase III studies varied from 4.1-4.3 months (prostate cancer) to 9.7 months (melanoma).
Administration of DC-based vaccines proved to be well tolerated. The promising, albeit still limited clinical success, justifies further exploration of DC vaccination in the most appropriate setting for each cancer type and will focus on administration route and the discovery of selection criteria for patients who are likely to benefit from DC vaccination. Moreover, increasing evidence suggests that DC vaccines should be used in a combinatorial approach with chemotherapy or other treatment modalities.

C'est quoi?

Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system. The DC vaccination strategy usually requires that DC precursors (peripheral blood monocytes or bone marrow derived stem cells) be collected from the patient and differentiated into DCs in vitro. Subsequently, these ex vivo generated DCs are loaded with tumour associated antigens (TAAs) and re-injected in the patient. The rationale behind vaccination with TAA loaded-DCs in cancer therapy is that injected DCs will induce a tumour-specific immune response resulting in tumour shrinkage or clearance.


2.1 Vaccine compositions

Three types of DCs are in use for clinical studies: monocyte-derived DCs, stem cell-derived DCs and circulating myeloid DCs directly obtained from the blood circulation (density-enriched DCs). Each DC type has its own characteristics and the impact of the DC type on final clinical outcome of the therapy is still being explored. Most studies carried out to date make use of autologous DCs derived from monocytes (1), although some studies used allogeneic DCs from a healthy donor.(2-5)
The clinical impact of DC vaccination also relies on the maturation status of the DCs. Different maturation protocols are in use, which bring about big differences in the degree of DC maturation. This summary occasionally discriminates between immature en mature DCs, but does not focus on any differences amongst the mature DCs. Responses to mature DCs are grouped.
Different methods for tumour antigen loading are in use. DCs can be loaded with well-defined TAA using peptides, proteins and nucleic acids, possibly with the help of heat shock proteins or viral vectors. Alternatively, whole tumour-derived material such as tumour lysates, apoptotic/necrotic tumour cells, whole tumour derived RNA or DC-tumour cell fusions can be used.(1)


2.2 History

DCs were first described in de skin in 1868 and owe their name to their tree-like or dendritic shape (from the Greek “dendron” meaning tree).(6) The use of DCs in cancer therapy started in the late 1980s with the discovery of new technologies for collection and administration of blood cell subsets.(1) The first clinical study with DCs was in four patients with follicular B-cell lymphoma, performed at the Stanford University Medical Center (California, US) and published in 1996 in Nature Medicine.(7)


2.3 Claims of efficacy / mechanisms of action

Upon injection into the patient, DCs are expected to migrate to the secondary lymphoid organs where they come in contact with T lymphocytes (both CD4+ and CD8+ T cells) and natural killer cells. As a result of this complex cellular meeting, cytotoxic T-lymphocytes (CTLs) specific for the TAAs used to load the DCs are induced. Then the TAA-specific CTLs migrate to the tumour site where they carry out tumour rejection.(8,9)
For proper TAA-specific CTL production the DCs need to be capable of producing immunostimulatory cytokines and co-stimulatory molecules in parallel with antigen presentation.(10) These properties are dependent on the activation stimuli used for their growth, maturation, and functional adjustment. A description of the various ex vivo DC generation protocols is, however, beyond the scope of this summary.
DCs have mostly been given intravenously, intradermally, and subcutaneously, although in some studies injections into a lymph node or directly into the tumour were performed. Weekly, biweekly and monthly vaccinations with DCs have all been reported, and normally DC immunizations have been performed in the studies until disease progression.(1) The numbers of DCs injected vary from 2 to100 million cells per injection.(6)


2.4 Legal issues

Provenge® or Sipuleucel-T from Dendreon received the first approval for a cell-based immunotherapy against prostate cancer in 2010 by the American Food and Drug Administration. The vaccine does not contain pure DC, but rather antigen pulsed activated peripheral blood mononuclear cells.(11) Other DC companies are seeking approval by the European and US regulatory authorities for DC vaccines targeted at lymphoma,sarcoma, glioblastoma and acute myelogenous leukaemia.(12)


2.5 Cost(s) and expenditures

Treatment with Provenge® costs approximately $93000 for a full course.

Efficace?

Clinical responses are affected by the degree of tumour load (measurable disease versus minimal residual disease). Clinical responders to DC vaccination had early-stage cancer or minimal residual disease at the time of DC administration.(13,24,25) Mature DCs did usually perform better than immature DCs.(13) Complete remissions or partial remissions were observed in a minority of patients. A greater proportion of cancer patients presented with long-term disease stabilization resulting in prolonged survival.(24,25,44) Since many of the TAA-specific immune responses that were induced upon DC vaccination did not correlate with any clinical response (32,35,56,63), new ways to increase the magnitude of tumour-specific immune responses are desirable.

 

3.1 Melanoma

Nakai et al. performed a review of 54 trials including 967 melanoma patients to evaluate the relationship between clinical effects of DC vaccination and vaccine parameters.(13) With the exception of one randomized phase III study in 108 patients with metastatic melanoma (14) all trials were phase I/II clinical studies. Thirty-six trials targeted stage IV patients, 13 targeted stage III–IV patients, 3 targeted stage II–IV patients, 1 targeted stage II patients only, and in 1 trial the disease stage was unclear. In 34 trials DC vaccination was combined with adjuvants (IL-2, GM-CSF, IFNa-2b, CTLA-4 antibodies, KLH or helper antigens), the other studies used adjuvant-free DC vaccination.
Objective responses (complete and partial response) for stages III and IV were similar (7.7 versus 7.3%) but the disease control rate (including stable disease in addition to complete and partial responses) was higher in stage III than stage IV (34.6 versus 23.5%; p = 0.03). A difference in progressive disease cases was found among stages II–IV (P = 0.0001). These results partly support validity of DC vaccination in patients with early-stage melanoma.(13) While the phase III trial, encompassing the highest number of patients with metastatic stage IV melanoma, could not demonstrate an overall survival advantage of patients treated with the DC-based vaccine over those treated with chemotherapy (dacarbazine), an exploratory subset analysis showed that the HLA-A2+/HLA-B44- patients receiving DC vaccination displayed a 9.7-months survival benefit compared to HLA-A2+/HLA-B44- patients receiving chemotherapy. In addition, vaccinated patients with the HLA-A2+/HLA-B44- HLA survived significantly longer than patients displaying another haplotype, while no correlation with HLA haplotype was found in the chemotherapy group.(14)
In the majority of the trials (49/54) monocyte-derived DCs were used, while the other 5 trials used stem cell-derived DCs. Thirty-three of the trials were performed with mature DCs (mDCs), 18 with immature DCs (iDCs). In one trial, mDCs and iDCs were administered to the same patients, and in two trials, mDCs or iDCs were separately administered to each patient. Clinical effects were related to the maturation status of the DCs. The objective response rate was higher in studies with peptide-pulsed DCs (7.8%) and in trials using iDCs as compared to mDCs (9.4 versus 6.0%, p = 0.13). The disease control rate was higher in studies with DC/tumour cell fusion products (30.9%) and in trials using mDCs as compared to iDCs (24.4 versus 20.8%, p = 0.64). The difference in responses to the use of iDCs versus mDCs only reached significance for progressive disease (p = 0.01). These results suggest that mDCs may be superior for maintenance of stable disease, disease-free status, and prevention of disease progression.
The objective response rate (11.7%) and disease control rate (27.7%) were measured as highest for the intranodal route, but the type of response did not differ significantly among the various injection routes (intradermal, subcutaneous, intranodal, intravenous, intralymphatic).
DC-based vaccination strategies are further explored with promising results (15,16) and very broad CD8+ and CD4+ TAA-specific T cell responses in both peripheral blood and skin.(17) From a retrospective analysis of one of the previous phase II studies Ridolfi et al. speculated that prior DC vaccination may improve response rate to other therapies that are initiated after stopping DC vaccination (surgery, radiotherapy, chemotherapy amongst others).(18)

3.2 Prostate cancer and renal cell carcinoma

Draube et al. performed a systematic review and meta-analysis of DC vaccination in prostate cancer and renal cell carcinoma (RCC).(19) Seventeen trials involving a total of 720 prostate cancer patients and 12 trials involving a total of 186 RCC patients were included (trials with < 6 patients were excluded). Apart from three randomized phase III studies with Sipuleucel-T in prostate cancer (20-22) all trials were phase I/II clinical studies. The median patient number within the phase I/II studies was 14 for prostate cancer (range 6–31) and 12 for RCC (range 8–35). The number of prostate cancer patients participating in the placebo-controlled phase III trials of Small et al., Higano et al. and Kantoff et al. were 82, 65 and 341, respectively.
In the prostate cancer trials, 662 patients had metastatic disease, 51 had biochemical relapse and 7 displayed local recurrence. Eighty-seven percent of prostate cancer patients had prior surgery or radiotherapy, 17% prior chemotherapy, and 96% prior hormone therapy or castration. In one prostate cancer trial all patients received IFN-g simultaneously. The histological RCC subtype was clear cell in the vast majority of participants. All RCC patients had metastatic disease. Ninety-two percent of RCC patients had prior surgery or radiotherapy, 17% prior chemotherapy and 36% prior immunotherapy. In 36% of RCC patients systemic IL-2 or IL-2/IFN-a was simultaneously applied to the DC vaccine. In one study, IL-2 was given immediately after the last vaccination. In two studies, 3 and 6 patients, respectively, received IL-2, IL-2/IFN-g or IL-2/IFN-g/5-FU after the end of the vaccination period. Pulsing of DCs with defined peptides or proteins was the preferred antigen loading strategy in the prostate cancer trials, whereas in RCC it was pulsing with tumour cell lysates.
Analysis of clinical responses revealed an objective response (complete, partial or mixed response) in 7.7% and 12.7% prostate cancer and RCC patients, respectively. When including the number of patients with stable disease a disease control rate of 54% and 48% was found in prostate cancer and RCC, respectively (see figure 1). A statistically significant association was demonstrated between clinical response and induction of a TAA-specific cellular immune response in in vitro functional tests, both in prostate cancer (odds ratio 10.6) and in RCC (odds ratio 8.4) (see figure 2). Moreover, a dose-response relationship was demonstrated.(17) The placebo-controlled phase III trials demonstrated a trend for survival advantage in asymptomatic hormone refractory prostate cancer patients (20), an overall survival benefit of 4.3 months (p = 0.011) in advanced prostate cancer patients (21) and a 4.1-month improvement of medium survival (p = 0.03) in castration-resistant prostate cancer patients (22). Kraemer et al. demonstrated that RCC patients participating to 3 phase I/II trials and with stable disease after DC vaccination showed the longest survival, with a mean of 88 months and a range between 25 to 164 months.(23)

Figure 1. Objective response rate (black columns) and disease control rate (grey columns) upon DC vaccination in prostate cancer and RCC patients. CR, complete response; PR, partial response; MR, mixed response; SD, stable disease. Source: Draube A, Klein-González N, Mattheus S et al. PLoS One 2011; 6(4):e18801.

Figure 2. Meta-analysis of the odds ratio (OR) of cellular immune response targeted against the tumour and clinical response. Source: Draube A, Klein-González N, Mattheus S et al. PLoS One 2011; 6(4):e18801.

 

Most prostate cancer patients received density-enriched DC, which was due to the larger phase III trials, whereas most RCC patients received mature monocyte-derived DCs. Immature monocyte-derived DCs were used in a smaller number of patients. In prostate cancer, vaccination with mature monocyte-derived DCs was associated with a higher clinical benefit rate than vaccination with immature monocyte-derived DCs.(19)
Intravenous route or a combination of different routes was the most frequently used strategy in the prostate cancer trials, whereas a non-intravenous route (intranodal, intradermal, subcutaneous) was chosen in the majority of RCC trials. The analysis of Draube et al. revealed a positive influence on clinical response of a non-intravenous route (intradermal, intralymphatic, subcutaneous or intranodal) compared with an intravenous route for monocyte-derived DC in both cancers, reaching statistical significance only in prostate cancer.(19)
Some trials used allogeneic DCs derived from normal donors in an attempt to increase vaccine efficacy. (3,5) However, the immunogenicity of allogeneic monocyte-derived DCs was found to be less pronounced than that of autologous monocyte-derived DC immunotherapy.(3)

3.3 Brain cancers

Vauleon et al. performed a review of 19 trials (2 case reports, 11 phase I studies, 5 phase I/II trials and 1 phase II study) involving a total of 313 patients with gliomas, mainly glioblastoma multiforme or anaplastic astrocytoma.(24) Kim et al. reviewed 16 of the above-mentioned trials in a narrative style.(25) In all but one study with concomitant IL-12 usage, adjuvant-free monocyte-derived DC vaccination was performed. Vaccines were injected intradermally or subcutaneously. In one study, 5 patients also received intracerebral injections. Preliminary findings from these trials argue for the need for maximal tumour resection or prior achievement of minimal residual disease status to improve the efficacy of DC vaccination in gliomas. Results from some of these small-scale trials suggested median improvements in survival of 23.4 months (n = 12), 198 days (n = 9), 103 weeks (n = 14) and 212 days (n = 34). One study showed that patients vaccinated with mature DC had better survival than those vaccinated with immature DC. Increased time to progression (TTP) of the cancer is another measure of the efficacy of DC vaccination in gliomas: increased TTPs of 15.5 months (n = 12) and 141 days (n = 34) have been found. Among the 130 patients (10 different studies) for whom the clinical response was measured 6 showed a complete response, 11 had a partial response, 7 displayed a mixed response and 27 developed stable disease. From the largest cohort of patients reported (n = 34), it was shown that responders to vaccination exhibited a better response to chemotherapy delivered in a second phase.
Prins et al. recently reported the 1-, 2-, and 3-year survival rates for newly diagnosed glioblastoma patients to be 93%, 77% and 58%, respectively provided they integrate DC vaccination in their treatment regimen of surgery, radiotherapy and chemotherapy.(26) Fadul et al. reported a mean progression-free survival of 9.5 months and overall survival of 28 months upon DC vaccination (after radiation chemotherapy) in 10 patients with glioblastoma multiforme.(26) Chang et al. found a median survival and 5-year survival of 525 days and 18.8%, respectively, for 16 patients with grade IV glioma (381 days and 12.5% for eight newly diagnosed; 966 days and 25% for eight relapsed patients) compared to 380 days and 0% for 63 historical control patients.(27)

3.4 Haematological cancers

 

Leukaemia

Persistence of residual leukaemia cells in acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML) will eventually lead to a relapse of the disease. DC vaccination is considered a therapeutic option for leukaemia patients to control or eradicate minimal residual disease, and to reduce relapse rates. Since DCs originate from the same precursor as AML and CML cells, an alternative approach for DC generation was investigated: leukaemia cell-derived DCs. Because of their tumour origin these ex vivo generated DCs are irradiated prior to administration. The approach seemed only feasible in a subgroup of patients (e.g. 60% of AML patients). In six small clinical trials performed from 2003 to 2007 and including a total of 19 CML patients and 41 AML patients the following problems were encountered: insufficient cell numbers in the leukaemia cell harvest, failure of leukaemia cells to undergo DC differentiation and failure to achieve complete remission, progressive disease or death before vaccination.(29-31) Monocyte-derived DCs have been chosen as an alternative for AML and CML patients in whom no DCs could be cultured out of leukaemic cells. Autologous monocytes are obtained when patients reach complete remission. Lee et al. report preliminary results from DC vaccination in 2 patients with relapsing AML after autologous stem cell transplantation. DC therapy induced a tumour-specific immune response (measurable in vitro), but could not reduce the percentage of tumour cells in bone marrow.(32) Van Tendeloo et al. performed a phase I/II trial in 10 AML patients. Two patients in partial remission after chemotherapy were brought into complete remission after DC vaccination. In 5 patients (including the former 2) the complete remission state was further stabilized, since a well-known AML-associated tumour marker returned to normal values upon DC vaccination. The vaccinated patients had increased levels of TAA-specific CD8+ T cells.(33) Takahashi could not detect any clinical response to DC vaccination in 3 CML patients in chronic phase 1.(34) Fifteen asymptomatic CML patients participating in the cohort study of Palma et al. also did not obtain any objective clinical response, but 10/15 were defined as immune-responders. The frequency of immune-responding patients was highest if the DC vaccine was combined with concomitant administration low-dose cyclophosphamide (chemotherapy).(35)
Vaccination with allogeneic monocyte-derived DCs is considered another option. The use of allogeneic monocyte-derived DCs is limited to patients who have an HLA-matched donor (unrelated, brother, sister). Hus et al. performed a feasibility study for DC vaccination in 9 previously untreated patients with B-cell chronic lymphocytic leukaemia (B-CLL) in early stages. In most patients a decrease of leukemic cells was observed in the first 5 days after this allogeneic DC vaccination. In 4 patients the disease remained stable over 23 months. In one patient a significant increase of TAA-specific cytotoxic T lymphocytes could be detected after DC vaccination.(36)

Multiple myeloma

High-dose chemotherapy followed by stem cell transplantation can produce higher remission rates and prolongs survival of multiple myeloma patients, but the great majority of the patients are not cured. Therefore, DC vaccination is considered a valuable therapeutic option once the patients are in complete (or partial) remission. Six clinical trials (feasibility studies, phase I, phase I/II) were performed during the time period of 2002-2011 in which a total of 67 multiple myeloma patients were treated with DC vaccination.(37-42) The patients were characterized as having stage I disease, stable partial remission or complete remission. The DCs were matured, monocyte-derived and administered subcutaneously and/or intravenously. In all but two studies KLH (a highly immunogenic protein) was used as adjuvant. A TAA-specific cellular immune response was demonstrated in 33 of 63 assessable patients after DC vaccination. According to the findings by Curti et al. the immune response was more robust after subcutaneous DC administration than after intravenous injections.(39) Within this variable patient group (of the 6 trials) some striking results were reported: one patient had disease improvement that persisted for 6 months (37), 2 patients remained in clinical partial remission during 25 months post-vaccination (38), 1 patient achieved durable partial remission for 40 months (39), 4 patients continued with stable disease at a 5-year follow-up (40), 3 patients with advanced disease had on-going stable disease at 12, 25 and 41 months.(41)
In 2009 Lacy et al. performed a phase II trial involving 27 multiple myeloma patients after autologous stem cell transplantation (ASCT) who were treated intravenously with a vaccine composed of antigen pulsed activated peripheral blood mononuclear cells (rather than pure DCs). Interestingly, the investigators also studied 124 historical controls (patients transplanted during the same period but not enrolled on the trial). The median overall survival for the trial patients was 5.3 years compared to 3.4 years for the control group (p = 0.02). Median time to progression and progression-free survival did not differ between both groups.(43)

Lymphoma

The first DC vaccination trial was performed in 4 patients with follicular B-cell lymphoma. All patients developed a measurable TAA-specific cellular immune response upon DC vaccination.(7) Timmerman et al. performed a clinical trial in which 35 patients with follicular B-cell lymphoma were treated with DC vaccination. Patients were either in remission or had residual tumour cells. The DCs were density-enriched and administered intravenously. Twenty-three of 33 assessable patients mounted a TAA-specific T cell immune response. Among 18 patients with residual tumour at the time of vaccination, 4 (22%) had tumour regression, and 16 of 23 patients (70%) remained without tumour progression at a median of 41 months after DC vaccination.(44)
Maier et al. evaluated the clinical response of DC vaccination in 10 patients with cutaneous T-cell lymphoma. The DCs were mature, monocyte-derived and administered intranodally. One patient had a complete response during a 19 months follow-up, 4 patients had a partial response (in 2 patients of 10.5 months’ duration), and the remaining 5 patients had progressive disease.(45)
Furthermore, a pilot study was performed in 18 indolent B-cell lymphoma patients with relapsed and measurable disease. The DC vaccine contained mature monocyte-derived DCs and was administered subcutaneously in close vicinity to axillary and inguinal lymph nodes. After DC vaccination 6 patients had objective clinical responses including 3 continuous complete responses and 3 partial responses, with a median follow up of 50.5 months. Eight patients had stable disease, whereas 4 had progressive disease.(46)

3.5 Breast cancer

Two phase I trials (47,48) and one phase II study (49) were performed in a total of 42 patients with metastatic breast cancer in order to evaluate the clinical effect of DC vaccination in conjunction with IL-2 therapy. The patients were heavily pre-treated with either chemotherapy, endocrine treatment regimens or radiotherapy (but not within 4 weeks prior to the DC therapy). The DCs were monocyte-derived and administered subcutaneously. Disease stabilization was attained in 13 patients, 1 patient presented with a mixed response, 1 patient developed a near complete response, while 27 patients had progressive disease. The success rate of tumour specific immune responses in in vitro functional tests was higher in patients presenting with disease stabilization as compared to those with progressive disease. The four breast cancer patients (stage IIb~IV) who participated in a phase I/II trial with stem cell-derived DCs (plus adjuvants: KLH and IL-2) were still displaying progressive disease after DC vaccination despite increases in NK cell activity and KLH specific immune responses.(50) Since it would be easier to expand a memory pool of T cells compared to generating new immunity Met et al. proposed to implement a pre-vaccination screening of patients for any pre-existence of immunity against the TAA to be used in the DC vaccine.(51)
Preliminary results from a pilot trial in which subjects with ductal carcinoma in situ (DCIS), a pre-invasive malignancy of the breast, were treated with DCs showed a markedly decreased HER-2/neu expression in 7 of 11 evaluable patients and an apparent tumour regression in 6/11. The vaccines were administered into a single lymph node in each groin.(52) A decline and/or eradication of HER-2/neu expression upon DC vaccination was confirmed in the pilot trial by Sharma et al., involving 27 DCIS patients after four intranodal administrations of monocyte-derived DCs at weekly intervals. The DC vaccination was more effective in oestrogen receptor negative (ERneg) than oestrogen receptor positive (ERpos) DCIS: sustained HER-2/neu expression was found in 10% of ERneg subjects compared with 47.1% in ERpos subjects (P = 0.04).(53) TAA-specific T cell immune responses were observed up to 52-month post-immunization.(54) Qi et al. evaluated the impact of a monocyte-derived DC vaccine in 31 patients with oestrogen receptor/progestin receptor double-negative breast cancer (stage II/IIIA). They reported a significantly prolonged 3-year progression-free survival after DC vaccination: 76.9% versus 31.0% (with vs. without DC vaccine, p < 0.05).(55)


3.6 Colorectal cancer

In 2006 Nagorsen and Thiel performed a systematic review with a meta-analysis of DC vaccination in patients with advanced colorectal cancer. At the time 10 small-scale phase I/II trials involving a total of 70 patients could be included. They found a disease control rate (sum of stable disease, complete, partial and mixed responses) of 17% (12/70). After DC vaccination TAA-specific cellular immune responses were demonstrated in in vitro functional tests in 53% of evaluable patients (20/38).(56)
Four additional trials with monocyte-derived DCs in patients with metastatic colorectal cancer were identified. Tamir et al. performed a phase I trial in which 8 patients with liver metastases received intranodal DC vaccination. Partial or complete stabilization of carcinoembryonic antigen (CEA) expression was shown in 4 patients. CEA, a membrane protein that is overexpressed in most colorectal cancers, positively correlates with disease progression. Initial tumour specific immune responses were lost towards the end of the trial (6 weeks).(57) Kavanagh et al. reported a lack of clinical activity of intradermal DC vaccination in a phase I/II trial in 13 patients.(58) Burgdorf performed a phase I/II trial in which 17 patients received intradermal DC vaccination. Four patients (24%) achieved stable disease (SD), and two of these remained stable throughout the entire study period of one year. In these patients with stable disease the DC based vaccine had initiated favourable anti-cancer responses of the immune system, indicated by positive results in in vitro functional tests. Taking all participants into account median survival from inclusion to the trial was 5.3 months (range 0.2-29.2 months).(59) Barth et al. performed a clinical trial in which 26 patients who had undergone resection of colorectal metastases were treated with intranodal DC vaccination. This treatment induced TAA-specific cellular immune responses in 15 of 24 assessable patients (63%). Patients with evidence of a vaccine-induced tumour-specific immune response 1 week after vaccination, had a markedly better recurrence-free survival at 5 years than non-responders (63% versus 18%, p = 0.037).(60)
Lesterhuis et al. performed an exploratory study in which 7 patients with stage III colon cancer received DC vaccination in combination with standard oxaliplatin/capecitabine chemotherapy. In 4 patients TAA-specific T cell immune responses were found, while oxaliplatin administration induced a non-specific T cell immune response in all patients.(61)

3.7 Liver cancer

In 2003 Ywashita et al. performed a phase I feasibility study in which 10 patients with unresectable primary liver cancer were treated with DC vaccination. Immature monocyte-derived DCs were administered into the groin lymph node. In one patient, one of the two liver tumours decreased in size (from 13 to 7 mm). In two patients DC vaccination induced a fall in the serum level of well-known tumour markers.(62) Vaccination with immature monocyte-derived DCs was combined with radiotherapy in a phase I study involving 14 patients with locally advanced or metastatic hepatoma. DCs were injected directly into the tumour. There were 2 partial responses and 4 minor responses. Three patients had a 50% decrease in the serum level of a tumour marker and 8 of 10 assessable patients showed a TAA-specific immune response.(63)
Two clinical trials evaluated the clinical response of intravenous DC vaccination with mature monocyte-derived DCs in patients with advanced hepatocellular carcinoma. Lee et al. enrolled 31 patients, 14 of them underwent basic therapy while 17 patients received monthly boost vaccinations on top of the basic therapy. Among the 31 patients, 4 (12.9%) exhibited a partial response, 17 (54.8%) had stable disease and 10 (32.3%) had progressive disease. The overall 1-year survival rate of all 31 patients was 40.1 ± 9.1%. Patients treated with the boosted therapy had better 1-year survival rates than those treated with the basic therapy alone (63.3 ± 12.0% versus 10.7 ± 9.4%, p < 0.001).(64) Palmer et al. performed a phase II study involving 35 patients, 25 of them were evaluable for a clinical response. The disease control rate (sum of partial response and stable disease) was 28%. In 4 out of 17 patients tumour marker serum levels fell to less than 30% of baseline values following vaccination.(65)

3.8 Lung cancer

Chang et al. performed a pilot feasibility trial for DC vaccination in 8 late-stage non-small-cell lung carcinoma (NSCLC) patients. Two patients with stable disease had the best tumour-specific T cell immune responses measured in vitro.(66) A phase I trial in 5 patients with advanced NSCLC showed a temporally improvement in tumour-specific immune response after DC vaccination. Two patients had a survival almost twice greater than the expected average.(67)
A feasibility study for DC vaccination in 10 patients with malignant pleural mesothelioma showed induction of tumour-specific immune responses in a subgroup of 5 patients. Three patients showed partial responses after DC vaccination, one showed stable disease, and six had no response.(68)
Wojas-Krawceyck et al. reported a prolonged disease-free survival (> 16 months from first vaccination) in 1 patient with lung adenocarcinoma who received subcutaneous injections with a monocyte-derived DC vaccine.(69)

3.9 Other cancers

Small-scale studies demonstrated that DC vaccination is also feasible for thyroid cancer (medullary thyroid carcinoma (70,71), advanced thyroid papillary/follicular cancer (72)), gynaecological cancers (ovarian cancer (73-75), cervical cancer (81-85), uterine cancer (68,86)), gastrointestinal cancers other than colorectal (87-90), pancreas cancer (91,92), and chondrosarcoma (93). After DC vaccination tumour-specific immune responses have been found in a subset of cancer patients, and while most patients had progressive disease (characteristic to the advanced stage of the disease) partial responses as well as disease stabilizations were reported.

 

Sans danger?

DC vaccination was well tolerated throughout the different clinical trials across all variations in treatment protocols, with only minor and mild side effects usually occurring for 1 or 2 days: chills, fever, asthenia, headache, tremor, dyspnoea, vomiting and local injection-site reactions.(20-22,24,25,94) Less common side effects were myalgias, fatigue, bone or articular pains.(17) Bahl et al. described the occurrence of a subclinical decline in cardiac ejection fraction in 3 of 27 breast cancer patients after HER-2/neu targeted DC vaccination.(95)

A notable exception was one brain cancer patient who experienced a grade IV neurotoxicity (stupor) due to DC vaccine-induced peri-tumoural oedema from a large residual tumor.(24,25)

Sporadic cases of treatment-related autoimmune phenomena, such as vitiligo, have been reported after DC vaccination.(6) Some degree of auto-immunity is considered beneficial for DC vaccine efficacy.(11)

References

References

1. Ballestrero A, Boy D, Moran E et al. Immunotherapy with dendritic cells for cancer. Adv Drug Deliv Rev 2008; 60(2):173-83.
2. Avigan DE, Vasir B, George DJ et al. Phase I/II study of vaccination with electrofused allogeneic dendritic cells/autologous tumor-derived cells in patients with stage IV renal cell carcinoma. J Immunother 2007; 30(7):749-61.
3. Höltl L, Ramoner R, Zelle-Rieser C et al. Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide. Cancer Immunol Immunother 2005; 54(7):663-70.
4. Kugler A, Stuhler G, Walden P et al. Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nat Med 2000; 6(3):332-6.
5. Märten A, Renoth S, Heinicke T et al. Allogeneic dendritic cells fused with tumor cells: preclinical results and outcome of a clinical phase I/II trial in patients with metastatic renal cell carcinoma. Hum Gene Ther 2003; 14(5):483-94.
6. Eubel J, Enk AH. Dendritic cell vaccination as a treatment modality for melanoma. Expert Rev Anticancer Ther 2009; 9(11):1631-42.
7. Hsu FJ, Benike C, Fagnoni F et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 1996; 2(1):52-8.
8. Nencioni A, Grünebach F, Schmidt SM et al. The use of dendritic cells in cancer immunotherapy. Crit Rev Oncol Hematol 2008; 65(3):191-9.
9. Skalova K, Mollova K, Michalek J. Human myeloid dendritic cells for cancer therapy: Does maturation matter? Vaccine 2010 May 28. [Epub ahead of print]
10. Bonehill A, Tuyaerts S, Van Nuffel AM, Heirman C, Bos TJ, Fostier K, Neyns B, Thielemans K. Enhancing the T-cell stimulatory capacity of human dendritic cells by co-electroporation with CD40L, CD70 and constitutively active TLR4 encoding mRNA. Mol Ther 2008; 16(6):1170-80.
11. Tuyaerts S. Dendritic cell therapy for oncology roundtable conference. J Immune Based Ther Vaccines 2011; 9(1):1.
12. Lesterhuis WJ, Aarntzen EH, De Vries IJ et al. Dendritic cell vaccines in melanoma: from promise to proof? Crit Rev Oncol Hematol 2008; 66(2):118-34.
13. Nakai N, Hartmann G, Kishimoto S, Katoh N. Dendritic cell vaccination in human melanoma: relationships between clinical effects and vaccine parameters. Pigment Cell Melanoma Res 2010; 23(5):607-19.
14. Schadendorf D, Ugurel S, Schuler-Thurner B et al; DC study group of the DeCOG. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol 2006; 17(4):563-70.
15. Wilgenhof S, Van Nuffel AM, Corthals J et al. Therapeutic vaccination with an autologous mRNA electroporated dendritic cell vaccine in patients with advanced melanoma. J Immunother 2011; 34(5):448-56.
16. Lesterhuis WJ, Schreibelt G, Scharenborg NM et al. Wild-type and modified gp100 peptide-pulsed dendritic cell vaccination of advanced melanoma patients can lead to long-term clinical responses independent of the peptide used. Cancer Immunol Immunother 2011; 60(2):249-60.
17. Van Nuffel AM, Benteyn D, Wilgenhof S, Corthals J, Heirman C, Neyns B, Thielemans K, Bonehill A. Intravenous and intradermal TriMix-dendritic cell therapy results in a broad T-cell response and durable tumor response in a chemorefractory stage IV-M1c melanoma patient. Cancer Immunol Immunother. 2012 Jul;61(7):1033-43. doi: 10.1007/s00262-011-1176-2. Epub 2011 Dec 10.
18. Ridolfi L, Petrini M, Fiammenghi L et al. Unexpected high response rate to traditional therapy after dendritic cell-based vaccine in advanced melanoma: update of clinical outcome and subgroup analysis. Clin Dev Immunol 2010; 2010:504979.
19. Draube A, Klein-González N, Mattheus S et al. Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis. PLoS One 2011; 6(4):e18801.
20. Small EJ, Schellhammer PF, Higano CS et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 24:3089–94.
21. Higano CS, Schellhammer PF, Small EJ et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115: 3670–9.
22. Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411–22.
23. Kraemer M, Hauser S, Schmidt-Wolf IG. Long-term survival of patients with metastatic renal cell carcinoma treated with pulsed dendritic cells. Anticancer Res 2010; 30(6):2081-6.
24. Vauleon E, Avril T, Collet B, Mosser J, Quillien V. Overview of cellular immunotherapy for patients with glioblastoma. Clin Dev Immunol 2010; 2010. pii: 689171.
25. Kim W, Liau LM. Dendritic cell vaccines for brain tumors. Neurosurg Clin N Am 2010; 21(1):139-57.
26. Prins RM, Soto H, Konkankit V et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res 2011; 17(6):1603-15.
27. Fadul CE, Fisher JL, Hampton TH et al. Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J Immunother 2011; 34(4):382-9.
28. Chang CN, Huang YC, Yang DM et al. A phase I/II clinical trial investigating the adverse and therapeutic effects of a postoperative autologous dendritic cell tumor vaccine in patients with malignant glioma. J Clin Neurosci 2011; 18(8):1048-54.
29. Westers TM, Ossenkoppele GJ, van de Loosdrecht AA. Dendritic cell-based immunotherapy in acute and chronic myeloid leukaemia. Biomed Pharmacother 2007; 61(6):306-14.
30. Van de Velde AL, Berneman ZN, Van Tendeloo VF. Immunotherapy of hematological malignancies using dendritic cells. Bull Cancer 2008; 95(3):320-6.
31. van den Ancker W, van Luijn MM, Westers TM et al. Recent advances in antigen-loaded dendritic cell-based strategies for treatment of minimal residual disease in acute myeloid leukemia. Immunotherapy 2010; 2(1):69-83.
32. Lee JJ, Kook H, Park MS, Nam JH, Choi BH, Song WH, Park KS, Lee IK, Chung IJ, Hwang TJ, Kim HJ. Immunotherapy using autologous monocyte-derived dendritic cells pulsed with leukemic cell lysates for acute myeloid leukemia relapse after autologous peripheral blood stem cell transplantation. J Clin Apher 2004; 19(2):66-70.
33. Van Tendeloo VF, Van de Velde A, Van Driessche A et al. Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci U S A 2010; 107(31):13824-9.
34. Takahashi T, Tanaka Y, Nieda M et al. Dendritic cell vaccination for patients with chronic myelogenous leukemia. Leuk Res. 2003; 27(9):795-802.
35. Palma M, Hansson L, Choudhury A et al. Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria. Cancer Immunol Immunother. 2011 Nov 16; DOI 10.1007/s00262-011-1149-5.
36. Hus I, Roliński J, Tabarkiewicz J et al. Allogeneic dendritic cells pulsed with tumor lysates or apoptotic bodies as immunotherapy for patients with early-stage B-cell chronic lymphocytic leukemia. Leukemia 2005; 19(9):1621-7.
37. Yi Q, Desikan R, Barlogie B, Munshi N. Optimizing dendritic cell-based immunotherapy in multiple myeloma. Br J Haematol 2002; 117(2):297-305.
38. Reichardt VL, Milazzo C, Brugger W et al. Idiotype vaccination of multiple myeloma patients using monocyte-derived dendritic cells. Haematologica 2003; 88(10):1139-49.
39. Curti A, Tosi P, Comoli P et al. Phase I/II clinical trial of sequential subcutaneous and intravenous delivery of dendritic cell vaccination for refractory multiple myeloma using patient-specific tumour idiotype protein or idiotype (VDJ)-derived class I-restricted peptides. Br J Haematol 2007; 139(3):415-24.
40. &Yi Q, Szmania S, Freeman J et al. Optimizing dendritic cell-based immunotherapy in multiple myeloma: intranodal injections of idiotype-pulsed CD40 ligand-matured vaccines led to induction of type-1 and cytotoxic T-cell immune responses in patients. Br J Haematol 2010; 150(5):554-64.
41. Rosenblatt J, Vasir B, Uhl L et al. Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma. Blood 2011; 117(2):393-402.
42. Röllig C, Schmidt C, Bornhäuser M et al. Induction of cellular immune responses in patients with stage-I multiple myeloma after vaccination with autologous idiotype-pulsed dendritic cells. J Immunother 2011; 34(1):100-6.
43. Lacy MQ, Mandrekar S, Dispenzieri A et al. Idiotype-pulsed antigen-presenting cells following autologous transplantation for multiple myeloma may be associated with prolonged survival. Am J Hematol 2009; 84(12):799-802.
44. Timmerman JM, Czerwinski DK, Davis TA et al. Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood 2002; 99(5):1517-26.
45. Maier T, Tun-Kyi A, Tassis A et al. Vaccination of patients with cutaneous T-cell lymphoma using intranodal injection of autologous tumor-lysate-pulsed dendritic cells. Blood 2003; 102(7):2338-44.
46. Di Nicola M, Zappasodi R, Carlo-Stella C et al. Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunologic responses in indolent B-cell lymphoma patients with relapsed and measurable disease: a pilot study. Blood 2009; 113(1):18-27.
47. Avigan D, Vasir B, Gong J et al. Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunological and clinical responses. Clin Cancer Res 2004; 10(14):4699-708.
48. Svane IM, Pedersen AE, Johnsen HE et al. Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study. Cancer Immunol Immunother. 2004; 53(7):633-41.
49. Svane IM, Pedersen AE, Johansen JS et al. Vaccination with p53 peptide-pulsed dendritic cells is associated with disease stabilization in patients with p53 expressing advanced breast cancer; monitoring of serum YKL-40 and IL-6 as response biomarkers. Cancer Immunol Immunother 2007; 56(9):1485-99.
50. Baek S, Kim CS, Kim SB, Kim YM, Kwon SW, Kim Y, Kim H, Lee H. Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial. J Transl Med 2011; 9:178.
51. Met O, Balslev E, Flyger H, Svane IM. High immunogenic potential of p53 mRNA-transfected dendritic cells in patients with primary breast cancer. Breast Cancer Res Treat; 125(2):395-406.
52. Czerniecki BJ, Koski GK, Koldovsky U et al. Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. Cancer Res 2007; 67(4):1842-52.
53. Sharma A, Koldovsky U, Xu S, Mick R, Roses R, Fitzpatrick E, Weinstein S, Nisenbaum H, Levine BL, Fox K, Zhang P, Koski G, Czerniecki BJ. HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ. Cancer 2012 Jan 17. doi: 10.1002/cncr.26734.
54. Koski GK, Koldovsky U, Xu S, Mick R, Sharma A, Fitzpatrick E, Weinstein S, Nisenbaum H, Levine BL, Fox K, Zhang P, Czerniecki BJ. A novel dendritic cell-based immunization approach for the induction of durable Th1-polarized anti-HER-2/neu responses in women with early breast cancer. J Immunother 2012; 35(1):54-65.
55. Qi CJ, Ning YL, Han YS, Min HY, Ye H, Zhu YL, Qian KQ. Autologous dendritic cell vaccine for estrogen receptor (ER)/progestin receptor (PR) double-negative breast cancer. Cancer Immunol Immunother 2012 Jan 31.
56. Nagorsen D, Thiel E. Clinical and immunologic responses to active specific cancer vaccines in human colorectal cancer. Clin Cancer Res 2006; 12(10):3064-9.
57. Tamir A, Basagila E, Kagahzian A et al. Induction of tumor-specific T-cell responses by vaccination with tumor lysate-loaded dendritic cells in colorectal cancer patients with carcinoembryonic-antigen positive tumors. Cancer Immunol Immunother 2007; 56(12):2003-16.
58. Kavanagh B, Ko A, Venook A et al. Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides. J Immunother 2007; 30(7):762-72.
58. Burgdorf SK. Dendritic cell vaccination of patients with metastatic colorectal cancer. Dan Med Bull 2010; 57(9):B4171.
59. Barth RJ Jr, Fisher DA, Wallace PK et al. A randomized trial of ex vivo CD40L activation of a dendritic cell vaccine in colorectal cancer patients: tumor-specific immune responses are associated with improved survival. Clin Cancer Res 2010; 16(22):5548-56.
60. Lesterhuis WJ, de Vries IJ, Aarntzen EA et al. A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients. Br J Cancer 2010; 103(9):1415-21.
61. Iwashita Y, Tahara K, Goto S et al. A phase I study of autologous dendritic cell-based immunotherapy for patients with unresectable primary liver cancer. Cancer Immunol Immunother 2003; 52(3):155-61.
62. Chi KH, Liu SJ, Li CP et al. Combination of conformal radiotherapy and intratumoral injection of adoptive dendritic cell immunotherapy in refractory hepatoma. J Immunother 2005; 28(2):129-35.
63. Lee WC, Wang HC, Hung CF et al. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother 2005; 28(5):496-504.
64. Palmer DH, Midgley RS, Mirza N et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 2009; 49(1):124-32.
65. Chang GC, Lan HC, Juang SH et al. A pilot clinical trial of vaccination with dendritic cells pulsed with autologous tumor cells derived from malignant pleural effusion in patients with late-stage lung carcinoma. Cancer 2005; 103(4):763-71.
66. Perroud MW Jr, Honma HN, Barbeiro AS et al. Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study. J Exp Clin Cancer Res 2011; 30:65.
67. Hegmans JP, Veltman JD, Lambers ME et al. Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma. Am J Respir Crit Care Med 2010; 181(12):1383-90.
68. Wojas-Krawczyk K, Krawczyk P, Buczkowski J et al. Immunotherapy of lung adenocarcinoma patient with Peptide-pulsed dendritic cells: a case report. Arch Immunol Ther Exp (Warsz) 2012; 60(1):69-77.
69. Stift A, Sachet M, Yagubian R et al. Dendritic cell vaccination in medullary thyroid carcinoma. Clin Cancer Res 2004; 10(9):2944-53.
70. Papewalis C, Wuttke M, Jacobs B et al. Dendritic cell vaccination induces tumor epitope-specific Th1 immune response in medullary thyroid carcinoma. Horm Metab Res 2008; 40(2):108-16.
71. Kuwabara K, Nishishita T, Morishita M et al. Results of a phase I clinical study using dendritic cell vaccinations for thyroid cancer. Thyroid 2007; 17(1):53-8.
72. Hernando JJ, Park TW, Kübler K et al. Vaccination with autologous tumour antigen-pulsed dendritic cells in advanced gynaecological malignancies: clinical and immunological evaluation of a phase I trial. Cancer Immunol Immunother 2002; 51(1):45-52.
73. Chu CS, Boyer J, Schullery DS et al. Phase I/II randomized trial of dendritic cell vaccination with or without cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission. Cancer Immunol Immunother 2011 Oct 22; DOI 10.1007/s00262-011-1081-8.
74. Rahma OE, Ashtar E, Czystowska M et al. A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients. Cancer Immunol Immunother 2012; 61(3):373-84.
75. Peethambaram PP, Melisko ME, Rinn KJ, Alberts SR, Provost NM, Jones LA, Sims RB, Lin LR, Frohlich MW, Park JW. A phase I trial of immunotherapy with lapuleucel-T (APC8024) in patients with refractory metastatic tumors that express HER-2/neu. Clin Cancer Res 2009; 15(18):5937-44.
76. Hernando JJ, Park TW, Fischer HP, Zivanovic O, Braun M, Pölcher M, Grünn U, Leutner C, Pötzsch B, Kuhn W. Vaccination with dendritic cells transfected with mRNA-encoded folate-receptor-alpha for relapsed metastatic ovarian cancer. Lancet Oncol 2007; 8(5):451-4.
77. Homma S, Sagawa Y, Ito M, Ohno T, Toda G. Cancer immunotherapy using dendritic/tumour-fusion vaccine induces elevation of serum anti-nuclear antibody with better clinical responses. Clin Exp Immunol 2006; 144(1):41-7.
78. Loveland BE, Zhao A, White S, Gan H, Hamilton K, Xing PX, Pietersz GA, Apostolopoulos V, Vaughan H, Karanikas V, Kyriakou P, McKenzie IF, Mitchell PL. Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma. Clin Cancer Res 2006; 12(3 Pt 1):869-77.
79. Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L, Brugger W. Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood 2000; 96(9):3102-8.
80. Santin AD, Bellone S, Palmieri M et al. Human papillomavirus type 16 and 18 E7-pulsed dendritic cell vaccination of stage IB or IIA cervical cancer patients: a phase I escalating-dose trial. J Virol 2008 Feb;82(4):1968-79.
81. Wang X, Santin AD, Bellone S et al. A novel CD4 T-cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7-pulsed dendritic cells. Cancer Immunol Immunother 2009; 58(2):301-8.
82. Santin AD, Bellone S, Palmieri M, Ravaggi A, Romani C, Tassi R, Roman JJ, Burnett A, Pecorelli S, Cannon MJ. HPV16/18 E7-pulsed dendritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities. Gynecol Oncol 2006; 100(3):469-78.
83. Ferrara A, Nonn M, Sehr P, Schreckenberger C, Pawlita M, Dürst M, Schneider A, Kaufmann AM. Dendritic cell-based tumor vaccine for cervical cancer II: results of a clinical pilot study in 15 individual patients. J Cancer Res Clin Oncol 2003; 129(9):521-30.
84. Santin AD, Bellone S, Gokden M, Cannon MJ, Parham GP. Vaccination with HPV-18 E7-pulsed dendritic cells in a patient with metastatic cervical cancer. N Engl J Med 2002; 346(22):1752-3.
85. Santin AD, Bellone S, Ravaggi A, Roman JJ, Pecorelli S, Parham GP, Cannon MJ. Induction of tumour-specific CD8(+) cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer. Br J Cancer 2002; 86(1):151-7.
86. Sadanaga N, Nagashima H, Mashino K et al. Dendritic cell vaccination with MAGE peptide is a novel therapeutic approach for gastrointestinal carcinomas. Clin Cancer Res 2001; 7(8):2277-84.
87. Matsuda K, Tsunoda T, Tanaka H et al. Enhancement of cytotoxic T-lymphocyte responses in patients with gastrointestinal malignancies following vaccination with CEA peptide-pulsed dendritic cells. Cancer Immunol Immunother 2004; 53(7):609-16.
88. Aloysius MM, Takhar A, Robins A, Eremin O. Dendritic cell biology, dysfunction and immunotherapy in gastrointestinal cancers. Surgeon 2006; 4(4):195-210.
89. Tanaka F, Haraguchi N, Isikawa K et al. Potential role of dendritic cell vaccination with MAGE peptides in gastrointestinal carcinomas. Oncol Rep 2008; 20(5):1111-6.
90. Suso EM, Dueland S, Rasmussen AM et al. hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes. Cancer Immunol Immunother 2011; 60(6):809-18.
91. Bauer C, Dauer M, Saraj S et al. Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study. Cancer Immunol Immunother 2011; 60(8):1097-107.
92. Tabarkiewicz J, Radej S, Hus I et al. Dendritic cells based immunotherapy of patient with chondrosarcoma--case report. Folia Histochem Cytobiol 2008;46(2):165-70.
93. Finocchiaro G, Pellegatta S. Immunotherapy for glioma: getting closer to the clinical arena? Curr Opin Neurol 2011; 24(6):641-7.
94. Bahl S, Roses RE, Sharma A et al. Asymptomatic changes in cardiac function can occur in ductal carcinoma-in-situ patients following treatment with HER-2/neu-pulsed dendritic cell vaccines. Am J Surg 2009; 198(4):488-94.

Thérapie cellulaire dendritique

Traitement par cellules dendritiques

Thérapie par cellules dendritiques

Vaccination DC

Vaccination-DC

DC Vaccination

Vaccination des cellules dendritiques