Therapeutic cancer vaccines
Cornelis J.M. Melief, Thorbald van Hall, Ramon Arens, Ferry Ossendorp, Sjoerd H. van der Burg
Cornelis J.M. Melief, Thorbald van Hall, Ramon Arens, Ferry Ossendorp, Sjoerd H. van der Burg
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Review Series

Therapeutic cancer vaccines

Abstract

The clinical benefit of therapeutic cancer vaccines has been established. Whereas regression of lesions was shown for premalignant lesions caused by HPV, clinical benefit in cancer patients was mostly noted as prolonged survival. Suboptimal vaccine design and an immunosuppressive cancer microenvironment are the root causes of the lack of cancer eradication. Effective cancer vaccines deliver concentrated antigen to both HLA class I and II molecules of DCs, promoting both CD4 and CD8 T cell responses. Optimal vaccine platforms include DNA and RNA vaccines and synthetic long peptides. Antigens of choice include mutant sequences, selected cancer testis antigens, and viral antigens. Drugs or physical treatments can mitigate the immunosuppressive cancer microenvironment and include chemotherapeutics, radiation, indoleamine 2,3-dioxygenase (IDO) inhibitors, inhibitors of T cell checkpoints, agonists of selected TNF receptor family members, and inhibitors of undesirable cytokines. The specificity of therapeutic vaccination combined with such immunomodulation offers an attractive avenue for the development of future cancer therapies.

Authors

Cornelis J.M. Melief, Thorbald van Hall, Ramon Arens, Ferry Ossendorp, Sjoerd H. van der Burg

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Figure 3

Methods to overcome the hostility of the cancer microenvironment toward T cells.

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Methods to overcome the hostility of the cancer microenvironment toward ...
(A) T cell–suppressive mechanisms include the production of immunosuppressive cytokines (IL-10, TGF-β), inflammatory cytokines (IL-6), IDO, and NO, and recruitment of immunosuppressive macrophages (M2-type tumor-associated macrophages [TAMs]) and MDSCs. Cancer cells do not provide the necessary “danger” signals for DC activation, permitting T cell effector and memory cell induction. Thus, DCs are not properly polarized to induce such responses, leading to Treg induction, T cell anergy, and T cell deletion. Moreover, inhibitory checkpoint control molecules such as CTLA-4, PD-1, TIM3, or LAG3 are upregulated on chronically and improperly stimulated T cells. (B) T cell–immunosuppressive mechanisms are counteracted by Abs against immunosuppressive and inflammatory cytokines or their cognate receptors, T cell–stimulatory Abs against TNF receptor family members (CD27, CD40, CD134, and CD137), chemotherapeutics causing immunogenic cell death, or IDO inhibitors. Importantly, vaccination must induce proper effector CD4+ and CD8+ T cell generation in lymph nodes. The robust circulating effector T cells induced by these vaccines travel to tumor sites, where their activity can be optimized by appropriate combinatorial therapies.