Vaccination for cancer: Myth or reality

Abstract

May 19, 2021

Vaccination targeting infectious pathogens has profoundly impacted public health and has led to the eradication of diseases that have plagued human history. The development of therapeutic vaccines for cancer has been pursued over many years in effort to harness the selectivity and potency of the immune system with the promise of greater efficacy and safety than standard cytotoxic therapy. The unique potency of immune therapy was highlighted by the observation that allogeneic hematopoietic stem cell transplantation is uniquely curative for a subset of patients with hematologic malignancies due to the graft versus tumor effect mediated by alloreactive lymphocytes.¹ Vaccine platforms were developed in an effort to elicit tumor specific immune responses to target established malignancy and provide immunologic memory to prevent recurrence. Initial studies focused on the introduction of tumor associated antigens as peptides, proteins or whole tumor cells, or lysate most commonly in the setting of advanced disease.² While clinical trials demonstrated immunologic responses and anecdotal disease regression, therapeutic efficacy was not clearly seen and several randomized trials did not show benefit over standard therapy.³ As such, vaccination was often viewed as an unrealized promise subsequently displaced by other therapeutic strategies.

The efficacy of cancer immunotherapy has been recently transformed with the enhanced understanding of the immunoregulatory aspects of the tumor microenvironment.^{4, 5} The role of negative costimulatory signaling as a mediator of T cell exhaustion led to the development of checkpoint blockade as effective therapy for diverse malignancies, particularly when characterized by high mutational burden and the presence of tumor specific neoepitopes. In addition, CAR T cell therapy involving the ex vivo generation of effector cells with high levels of costimulatory molecule expression have received FDA approval for treatment of patients with lymphoma, acute lymphocytic leukemia, and multiple myeloma demonstrating a profound impact on a subset of patients with advanced disease. In this context, vaccine design has similarly evolved to incorporate this increased understanding of the complex interface between tumor cells and the immune environment to augment therapeutic efficacy, identify the optimal settings of intervention, and develop combinatorial approaches.

A critical factor for vaccine design is the identification of antigenic targets that are selectively expressed by malignant cells and potentially recognized by the T cell repertoire.⁶ These have included aberrantly expressed oncogenic proteins, tissue specific markers, and antigens characteristically expressed in fetal development that are upregulated in the setting of malignancy.⁷ While selection of antigen(s) is optimized when expression captures clonal diversity of the tumor, there has been growing appreciation of providing a platform of activation that facilitates epitope spreading to target cancer heterogeneity. In addition, efforts to enhance immunogenicity may involve generation of heteroclitic peptides that enhance T cell affinity.⁸ Neoepitopes arising from mutational events may be identified through computational platforms that are recognized as foreign and targeted by high affinity T cells that have not been subjected to central or peripheral tolerance mechanisms to protect against auto-immunity.^{9, 10}

Another critical factor for enhancing vaccine efficacy is the effective presentation of antigen in the context of co-stimulation through recruitment of mediators of innate immunity and antigen presentation. Dendritic cells (DCs) express high levels of costimulatory molecules and inflammatory cytokines necessary for activation and expansion of primary tumor specific immunity.¹¹ DCs may be recruited in vivo through the use of oncolytic or immunogenic viral vectors or cytokines such as GM-CSF.^12-15 Alternatively, the ex vivo generation of antigen presenting cells provides a critical platform the generation of effective immunity. Loading of individual tumor antigens onto DCs may be accomplished through the use of tumor associated peptides, proteins, or corresponding RNA or DNA.¹⁶ Alternatively, introduction of antigens derived from whole tumor cells have involved the use of tumor lysate, apoptotic bodies, allogeneic, and whole cell RNA. The relative immunologic potency of the different antigen platforms has not been fully elucidated but polyvalent vaccines may provide protection from tumor escape due to the emergence of antigen negative variants. We have developed hybridomas involving the fusion of patient derived tumor cells and autologous DCs capable of activating and expanding a diverse array of T cell clones targeting both shared and neoepitopes expressed by the malignant cell.^{16, 17} Further enhancement of the vaccine platforms has been explored through the incorporation of checkpoint blockade or immunostimulatory platforms such as biomatrices facilitating antigen presentation.

The development of next generation vaccine platforms has led to the heightened expansion of tumor reactive T cell clones. Clinical trials have demonstrated an association between immunologic response and disease response or time to progression.⁷ Of note, vaccination has been more recently largely pursued in the setting of low volume disease following cytoreduction to allow for the expansion of tumor reactive clones and minimize the immunoregulatory impact of a rapidly expanding tumor volume. Provocative results have been noted with respect to prolonged period of disease control but this has been difficult verify in large randomized clinical trials in which biologic diversity and a rapidly changing standard of care may also impact results.¹⁸ Of note, in one example vaccination did not result in a statistically significant difference in time to progression but did appear to be associated with prolongation of survival raising a fundamental question as to how to best assess the impact of immunomodulatory therapy on long term outcome.

The increased understanding of the complex nature of immune regulation and cancer immunity has also suggested that combinatorial strategies might be the optimal approach to reverse tumor mediated immune suppression to create long term disease control. Effective vaccine platforms have demonstrated the capacity to elicit the expansion and transient activation of tumor reactive clones. However, functional potency of these clones may be limited by negative immune regulation of the tumor microenvironment. In contrast, immunostimulatory agents such as checkpoint inhibition may require the presence of tumor reactive lymphocytes as a substrate for therapeutic efficacy. As such, the combination of vaccination with agents targeting critical aspects of the tumor microenvironment may be required to achieve therapeutic efficacy.^{19, 20} Similarly, immune effector cell therapy such as CAR T cells has shown short term potency in the setting of advanced disease where the antigenic target is not expressed on vital normal tissues. However, the hyper-stimulated nature of these cells may also result in disease escape due the induction of exhaustion and emergence of antigen negative variants. Vaccination may play a critical role in providing cyclic stimulation and facilitating epitope spreading for immune effector cells.²¹

The development of therapeutic cancer vaccines has yet to realize to its considerable potential likely due to the barriers of overcoming tumor mediated immune suppression and tolerance mechanisms. A fundamental challenge involves the induction of clinically meaningful immunity that discriminates between tumor cells and normal tissue in which the patterns of antigen expression may significantly overlap. However, vaccine mediated stimulation may provide more durable expansion of tumor reactive clones utilizing central pathways of adaptive immunity that when combined with immunoregulatory agents and effector cell activation may provide sustained protection against malignancy.