Utilization of influenza vaccination as an intratumoral immunotherapy for cancer

In recent years, immunotherapy for cancer has yielded unprecedented response rates and increased survival in patients. Despite progress, a significant fraction of patients exhibit progression of tumor growth during immunotherapy treatment. One barrier to response is the tumor microenvironment; patients who lack immune infiltration of their tumors or exhibit infiltration of suppressive cell subsets often do not respond to immunotherapy. In an effort to infiltrate the tumor microenvironment with pro-inflammatory cells (such as CD8+ T cells) that are correlated with response to immunotherapy in the clinic, inactivated influenza was administered intratumorally in immunocompetent mice. This vaccination slowed tumor growth when compared to that of mock-treated controls, and yielded an increased proportion in the tumor of dendritic cells, cross-presenting dendritic cells, CD8+ T cells, and tumor-reactive CD8+ T cells –all critical for anti-tumor immunity. Moreover, analysis of RNA from the vaccinated tumor revealed an upregulation in transcripts indicative of an inflamed tumor microenvironment, relative to that observed in mock-treated controls. Intratumoral influenza vaccination administered in combination with checkpoint blockade (αPD-L1) immunotherapy resulted in superior tumor control relative to that observed with either therapy alone. Further benefit derived from the intratumoral vaccination was protection from influenza infection. Interestingly, one vaccine formulation tested contained a squalene-based adjuvant; this vaccine did not slow tumor growth and failed to reduce the proportion of suppressive B regulatory cells (Bregs) in the tumor. Depletion of Bregs enabled the adjuvanted influenza vaccine to slow tumor growth. The research discussed in this dissertation indicates that intratumoral influenza vaccination may be used in the future as an immunotherapy for cancer; clinical trials are currently in preparation.Ph.D.Includes bibliographical reference