Senolytic Vaccine Slows Tumor Growth in Animal Models
Stressing cancer cells to induce a senescent state is a secondary goal of cancer therapy, after inducing cell death, as senescence brings a halt to replication. Senescent cell burden is an important component of degenerative aging, and so clearance of the senescent cells created by treatment following the completion of cancer therapy should be beneficial to patients. There is a complex relationship between the presence of senescent cells and the ability of a cancer to grow, however. Senescent cells draw the attention of the immune system, but also secrete signals that can help to support the growth of cancerous cells. There is some debate over whether one should expect clearance of senescent cells during cancer treatment to help or hinder the goal of eliminating the cancer. Here, researchers provide animal model data to suggest that removing senescent cells hinders cancer growth to some degree.
Immunologically mediated clearance of senescent cells has been demonstrated in several model systems. Given increasing evidence for these cells promoting tumor pathology and immune escape, we sought to examine whether a vaccine against senescent cells can lead to tumor regression. A senolytic dendritic cell (DC) immunotherapy ("SenoVax") was created by pulsing DC with cell lysate from senescent fibroblasts, producing DCs that expressed co-stimulatory molecules, stimulated T cell proliferation, and expressed the senescence antigen p16.
SenoVax induced prophylactic and therapeutic tumor regression in Lewis Lung Carcinoma (LLC) primary and metastatic murine tumor models. T cell proliferative and cytokine recall responses towards senescent cells but not to control stromal cell pulsed DCs were detected in vaccinated mice. Additionally, reduction in senescence associated biomarkers IL-11, IL-6, IL-23 receptor, and YLK-40 were observed. Adoptive transfer experiments revealed a role for CD8+ T cells in transplanting protection.
When SenoVax was administered in combination with anti-PD-L1 or anti-CTLA-4 antibodies, the data showed synergistic effects in reducing tumor growth. SenoVax also demonstrated reduction of glioma, pancreatic cancer, and breast cancer cell growth. No significant activation of complement or induction of autoantibodies was observed. The data provide mechanistic support for advancement of senolytic immunotherapy as a novel form of cancer therapy.