Optimization of Peptide Vaccines to Induce Robust Antitumor CD4 T-cell Responses

160

145

There are compelling arguments for designing cancer vaccines specifically to induce CD4+ helper T cell responses. Recent studies highlight the crucial role of proliferating, activated effector memory Th1 CD4+ T cells in effective antitumor immunity and reveal that CD4+ T cells induce more durable immune-mediated tumor control than CD8+ T cells. CD4+ T cells promote antitumor immunity by numerous mechanisms including enhancing antigen presentation, co- stimulation, T cell homing, T cell activation, and effector function. These effects are mediated at sites of T cell priming and at the tumor microenvironment. Several cancer vaccine approaches induce durable CD4+ T cell responses and have promising clinical activity. Future work should further optimize vaccine adjuvants and combination therapies incorporating helper peptide vaccines.

Section: Key Roles Of Tcd4 Lymphocytes In Anti-tumor Immune Responsesmentioning

confidence: 99%

Vaccines targeting helper T cells for cancer immunotherapy

Melssen

Slingluff

2017

160

145

“…The most significant issue for selecting a TAg is related to potential immune tolerance that could affect the quality of the T cell response (capacity to recognize the tumor cell). Nevertheless, there are examples of successfully eliciting anti-tumor T cell responses to “self-antigens”, when immune tolerance was predicted [18–21]. …”

Section: Antigen Selectionmentioning

confidence: 99%

“…Many of these peptides function as promiscuous epitopes (can be presented by several MHC-II alleles), potentially allowing their use as vaccines in broad patient populations. Following the model used with CTL vaccines, we reported the use of TriVax for eliciting substantive HTL responses in mice [21]. As with CTLs, the induction of HTLs by TriVax required a systemic prime-boost peptide administration and relied on IFN-I.…”

Section: Optimization Of Peptide Vaccinesmentioning

confidence: 99%

“…With a peptide derived from Trp1 (Trp1 113–127 ), TriVax was able to overcome immune tolerance and induced HTLs capable of recognizing and killing MHC-II-expressing (interferon-gamma treated) B16 melanoma cells. TriVax immunization with the Trp1 HTL epitope into mice with established B16 tumors resulted in significant reductions in the rate of tumor growth [21]. …”

Section: Optimization Of Peptide Vaccinesmentioning

confidence: 99%

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Cancer immunotherapy: moving forward with peptide T cell vaccines

Kumai

Fan

Harabuchi

et al. 2017

Self Cite

Recent advances in cancer immunology, such as the discovery of immune checkpoint inhibitors, have validated immune cells as potential key players for effective cancer treatment. The efficacy of these therapies seems to be codependent on a tumor-reactive T lymphocyte response. For many years, numerous attempts and strategies in developing vaccines to generate tumor-reactive T cells have yielded poor results in the clinic due to suboptimal immunogenicity and the inability to overcome an immunosuppressive tumor microenvironment. In this review, we summarize past and current advances in T cell vaccines and describe our experience in developing optimized methods for antigen/adjuvant selection and vaccine administration in order to induce powerful anti-tumor responses.

“…Notably, in the absence of co-stimulating PRR [19] or TCR [20], or stimulation prior to T cell receptor engagement ([••21]; our unpublished data), CD40 stimulation can have deleterious effects on CD8 + T cell responses. Conversely, the combination of TLR stimulation and CD40 stimulation has become the gold-standard in protein-based cancer vaccines in pre-clinical models, often generating a response where 20–40% of the CD8 + T cells in the immunized animal being specific for the vaccinating antigen, and targeting CD40/TLR in combination with vaccination has been successful in control established tumors in multiple mouse [11;22;••23]. In these studies, and in our experience, vaccination with anti-CD40 and peptide in the context of a TLR agonist is sufficient to drive large CD8+ T cell populations into tumors that were hitherto poorly infiltrated with T cells.…”

Section: Initiating the Cd8+ T Cell Responsementioning

confidence: 99%

TNF-receptor superfamily agonists as molecular adjuvants for cancer vaccines

Bullock

2017

Cancer vaccines have offered unrequited hope as a mechanism for rapidly and potently eliciting a patient’s immune system to counter tumors. Initial results from preclinical mouse models have not translated to substantial benefit to patients, suggesting that either the targets or the vaccination approach were inadequate. Recent innovations in antigen identification have spiked renewed interest vaccination technologies. This has coincided with a detailed molecular understanding of the coordinated steps in post-activation support of T cell proliferation, differentiation and survival, leading to the development of novel targets and combinations that are substantially more effective than first and second generation cancer vaccines in preclinical models. Within this cluster of developments, the TNF-receptor superfamily members have emerged as attractive candidates for clinical implementation. Here we review recent developments in the mechanisms of action of TNFRSF agonists, and how their activity is potentiated by integration co-targeting pattern recognition receptors.