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Dendritic cells in cancer immunotherapy: vaccines or autologous transplants?

ABSTRACT: Dendritic cells (DCs) are the most powerful immunostimulatory cells specialized in the induction and regulation of immune responses. Their properties and the feasibility of their large-scale ex vivo generation led to the application of ex vivo-educated DCs to bypass the dysfunction of endogenous DCs in cancer patients and to induce therapeutic anti-cancer immunity. While multiple paradigms of therapeutic application of DCs reflect their consideration as cancer "vaccines", numerous features of DC-based vaccination resemble those of autologous transplants, resulting in challenges and opportunities that distinguish them from classical vaccines. In addition to the functional heterogeneity of DC subsets and plasticity of the individual DC types, the unique features of DCs are the kinetic character of their function, limited functional stability, and the possibility to imprint in maturing DCs distinct functions relevant for the induction of effective cancer immunity, such as the induction of different effector functions or different homing properties of tumor-specific T cells (delivery of "signal 3" and "signal 4"). These considerations highlight the importance of the application of optimized, potentially patient-specific conditions of ex vivo culture of DCs and their delivery, with the logistic and regulatory implications shared with transplantation and other surgical procedures.

SUBMITTER: Kalinski P

PROVIDER: S-EPMC3695396 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Dendritic cells in cancer immunotherapy: vaccines or autologous transplants?

Kalinski Pawel P Edington Howard H Zeh Herbert J HJ Okada Hideho H Butterfield Lisa H LH Kirkwood John M JM Bartlett David L DL

Immunologic research 20110801 2-3

Dendritic cells (DCs) are the most powerful immunostimulatory cells specialized in the induction and regulation of immune responses. Their properties and the feasibility of their large-scale ex vivo generation led to the application of ex vivo-educated DCs to bypass the dysfunction of endogenous DCs in cancer patients and to induce therapeutic anti-cancer immunity. While multiple paradigms of therapeutic application of DCs reflect their consideration as cancer "vaccines", numerous features of DC ...[more]

PMID: 21717071

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Project description:BACKGROUND:Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient's mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA. METHODS:Short-term autologous tumor cell lines were established from metastatic tumor. Vaccines were admixed with 500 micrograms of GM-CSF and injected weekly for 3 weeks, then at weeks 8, 12,16, 20, and 24. The primary endpoint was overall survival. Secondary objectives were identification of adverse events, and results of delayed type hypersensitivity (DTH) reactions to intradermal tumor cell injections. RESULTS:Forty-two patients were randomized. All were followed from randomization until death or for five years; none were lost to follow-up. DCV was associated with longer survival: median 43.4 versus 20.5 months (95% CI, 18.6 to >?60 versus 9.3 to 32.3 months) and a 70% reduction in the risk of death (hazard ratio?=?0.304, p?=?0.0053, 95% CI, 0.131 to 0.702). Tumor DTH reactions were neither prognostic nor predictive. The most common treatment-related adverse events were mild to moderate local injection site reactions and flu-like symptoms; but grade 2 treatment-related adverse events were more frequent with TCV. Serum marker analyses at week-0 and week-4 showed that serum markers were similar at baseline in each arm, but differed after vaccination. CONCLUSIONS:This is the only human clinical trial comparing DCV and TCV as platforms for autologous TAA presentation. DCV was associated with minimal toxicity and long-term survival in patients with metastatic melanoma. DTH to autologous tumor cells was neither prognostic for survival nor predictive of benefit for either vaccine. TRIAL REGISTRATION:Clinical trials.gov NCT00948480 retrospectively registered 28 July 2009.

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Dendritic cells in cancer immunotherapy: vaccines or autologous transplants?

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Dendritic cells in cancer immunotherapy: vaccines or autologous transplants?

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