Therapeutic vaccination immunomodulation: forming the basis of all cancer immunotherapy

Abstract

Recent immunotherapy advances have convincingly demonstrated complete tumour removal with long-term survival. These impressive clinical responses have rekindled enthusiasm towards immunotherapy and tumour antigen vaccination providing ‘cures’ for melanoma and other cancers. However, many patients still do not benefit; sometimes harmed by severe autoimmune toxicity. Checkpoint inhibitors (anti-CTLA4; anti-PD-1) and interleukin-2 (IL-2) are ‘pure immune drivers’ of pre-existing immune responses and can induce either desirable effector-stimulatory or undesirable inhibitory-regulatory responses. Why some patients respond well, while others do not, is presently unknown, but might be related to the cellular populations being ‘driven’ at the time of dosing, dictating the resulting immune response. Vaccination is in-vivo immunotherapy requiring an active host response. Vaccination for cancer treatment has been skeptically viewed, arising partially from difficulty demonstrating clear, consistent clinical responses. However, this article puts forward accumulating evidence that ‘vaccination’ immunomodulation constitutes the fundamental, central, intrinsic property associated with antigen exposure not only from exogenous antigen (allogeneic or autologous) administration, but also from endogenous release of tumour antigen (autologous) from in-vivo tumour-cell damage and lysis. Many ‘standard’ cancer therapies (chemotherapy, radiotherapy etc.) create waves of tumour-cell damage, lysis and antigen release, thus constituting ‘in-vivo vaccination’ events. In essence, whenever tumour cells are killed, antigen release can provide in-vivo repeated vaccination events. Effective anti-tumour immune responses require antigen release/supply; immune recognition, and immune responsiveness. With better appreciation of endogenous vaccination and immunomodulation, more refined approaches can be engineered with prospect of higher success rates from cancer therapy, including complete responses and better survival rates.

Evaluation of T-Cell Responses Against Shared Melanoma Associated Antigens and Predicted Neoantigens in Cutaneous Melanoma Patients Treated With the CSF-470 Allogeneic Cell Vaccine Plus BCG and GM-CSF

“…TAAs like PMEL/gp100, tyrosinase, and several CT Ags have been identified as melanoma regression Ags (33,34). The roles of non-mutated TAAs were recently reinvigorated as key players in the endogenous anti-melanoma immunity (35,36) since they may be involved in either CM surveillance or dormancy. In our study, vaccination with the allogeneic CSF-470 vaccine has provided sustained targeting of TAAs.…”

Immunotherapy in the Treatment of Metastatic Melanoma: Current Knowledge and Future Directions

“…The first include biological medications such as cytokines, interferons, and granulocyte-monocyte colony-stimulating factors [ 54 ]. The second is the vaccination strategy based on peptide, on the whole protein, on virus, on DNA, or on DC [ 55 ]. The third group is based on adoptive cell therapy, which consists in the use of the so-called lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TIL), and other specific lymphocytes [ 56 , 57 ].…”

The Immune System and Responses to Cancer: Coordinated Evolution

“…It is now clear that the immune system is not ignorant to the presence of tumours, that it does recognise tumour antigens, and that the normal homeostatic regulatory mechanisms suppress active anti-tumour immune responses, and are at the seat of the problem. This explains why immuno-modulatory agents, such as IL2, and CTLA4, PD1/L1 monoclonal antibodies can deliver random dramatic complete responses in a limited percentage of late-stage cancer patients by releasing the pre-existing homeostatic suppression/tolerance 1,[125][126][127][128][129][130] . All of these immunotherapeutic agents can induce immune activation, but can also induce immune tolerance.…”