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.

Figure 3. Methods to overcome the hostility of the cancer microenvironment toward T cells.

(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.

Figure 2. Processing of vaccine-derived antigens.

For antigen loading in HLA class I molecules, antigen must enter the DC cytoplasm to be processed by the proteasome complex. Longer antigen fragments are cut down by the proteasome to smaller, 9– to 15–amino acid stretches that can be pumped through the transporter of antigen processing (TAP), thereby gaining access to the endoplasmic reticulum, where HLA class I loading with fragments of 9 to 12 amino acids takes place, followed by transport to the cell surface. For antigen loading in HLA class II molecules, the antigen must enter the endosomal system, where cathepsins digest the antigen, followed by loading of HLA class II with fragments of approximately 12 to 15 amino acids at low pH and, following DC maturation, transport to the cell surface. Once DCs have fully matured, they interact with CD8⁺ and CD4⁺ T cells by stimulating the TCR with antigen presented by HLA class I or II molecules, respectively, and costimulatory molecules such as CD28. Activated, primed CD8⁺ T cells are then capable of killing tumor cells via ligation of the TCR with antigen presented by HLA class I molecules.

Figure 1. Mode of action of therapeutic cancer vaccines.

Routes of vaccine administration and migration of immune cells. Antigen-loaded DCs (APCs) travel through the afferent lymph to the lymph nodes, where they prime T cells. The primed, activated T cells migrate through the efferent lymph, thoracic duct, and blood to reach tumor cells. Vaccine-induced T cells must engage with and overcome hostile elements in the cancer microenvironment, including immunosuppressive cells (Tregs, MDSCs) and factors released by the tumor cells, such as immunosuppressive chemokines and cytokines and IDO, which impair T cell migration, function, and expansion.