An Update on the Relevance of Vaccine Research for the Treatment of Metastatic Melanoma

Abstract

Past & present r In the past decade, the introduction of effective signal transduction inhibitors and anticheckpoint antibodies has significantly improved the prognosis for patients with metastatic melanoma, but the majority of such patients still die within 5 years. r Vaccine approaches designed to induce immunity to well-characterized melanoma-associated antigens, or to antigens expressed on allogeneic tumor cell lines, have not resulted in approved agents. r Despite the limitations associated with the immunosuppressive tumor microenvironment, there now is one intralesional autologous vaccine that has received regulatory approval for patients who have primarily soft-tissue metastases. Future r There are still unmet needs that may be met by therapeutic vaccines. r Successful vaccines likely will be those that induce or enhance recognition of patient-specific autologous neoantigens that result from nonsynonymous mutations contained in autologous tumor cells.Signal transduction inhibitors and anticheckpoint antibodies have significantly improved survival for metastatic melanoma patients, but most still die within 5 years. Vaccine approaches to induce immunity to well-characterized melanoma-associated antigens, or to antigens expressed on allogeneic tumor cell lines, have not resulted in approved agents. Despite the limitations associated with the immunosuppressive tumor microenvironment, there now is one intralesional autologous vaccine approved for patients who have primarily soft-tissue metastases. There is continued interest in patient-specific vaccines, especially dendritic cell vaccines that utilize ex vivo loading of autologous antigen, thus bypassing certain in vivo immunosuppressive cells and cytokines. Because of their mechanism of action and limited toxicity, they are potentially synergistic or additive to other antimelanoma therapies. A recent commentary concluded that there is a potential role for therapeutic vaccines in cancer therapy despite the clinical success of immune checkpoint inhibitors [1]. A similar conclusion previously was made for metastatic melanoma, in which it was argued that there is a strong rationale for therapeutic anticancer vaccines against metastatic melanoma even though to date no antimelanoma vaccines had been proven to be effective, and the best chance for success rested on approaches leading to recognition of autologous tumor cell antigens (tumor-associated antigen [TAA]) [2]. Furthermore, the suggestion that therapeutic vaccine research was no longer relevant because of the success of new targeted therapies including BRAF/MEK and immune-checkpoint inhibitors was refuted. The following is an update regarding these issues.

Patient-Specific Dendritic Cell Vaccines with Autologous Tumor Antigens in 72 Patients with Metastatic Melanoma

“…The checkpoint inhibitors anti-CTLA-4 (ipilimumab) and anti-PD-1 antibodies nivolumab and pembrolizumab as well as the combination of nivolumab plus ipilimumab have also been approved as first-line therapies for unresectable and distant metastatic melanoma, and as adjuvant therapies for patients with high risk stage 3 melanoma or resected stage 4 melanoma. However, there appears to still be an unmet need for vaccine strategies that can induce or enhance recognition of patient-specific ATA in addition to using checkpoint inhibitors to block factors that are suppressing existing immune responses [19,20].…”

PEGylated tumor cell membrane vesicles as a new vaccine platform for cancer immunotherapy

“…The immunotherapy breakthroughs over the past decade have recognized the previously suggested role of the immune system in fighting cancer, leading to the clinical approval of checkpoint blockade inhibitors, including αCTLA-4 and αPD-1 antibodies [2–4]. While tumor regression and complete cures have been seen with these approaches in many patients, the limited response rate to immune checkpoint blockade demonstrates the need for new complementary approaches [5]. …”

Multi-antigen Vaccination With Simultaneous Engagement of the OX40 Receptor Delays Malignant Mesothelioma Growth and Increases Survival in Animal Models

“…These fragments, referred to as tumor epitopes, represent targets for T cells that can specifically recognize the tumor cell for immune-mediated elimination. To minimize off-target effects that could lead to the development of autoimmunity, it is important to choose antigens that are not expressed or minimally detectable in normal tissues (23). In this regard, we also evaluated antigen expression in normal tissues in our laboratory as well as expression data from the literature (17, 18).…”