Date of Award

Spring 5-6-2019

Degree Type

Thesis

Degree Name

MS Biology

Department

Biology

Advisor

Joseph Gulfo, MD., MBA

Committee Member

Roberta Moldow, Ph.D.

Committee Member

Angela V. Klaus, Ph.D.

Keywords

Immunotherapy, Checkpoint inhibitors, combination treatment, anti-PD-1, anti-CD47, anti-SEMA4D

Abstract

Traditionally, cancer therapies are generally non-specific treatments meant to eradicate cancer cells. This can result in death of healthy tissue, which can significantly affect the overall well-being of the patient during and after treatment. Immunotherapy offers a more targeted approach by using immune cells to specifically identify and kill cancer cells through various neoantigens presented on the surface of the cancer cell. Drugs that target and block PD-(L)1 and CTLA-4, known as checkpoint inhibitors, act to “cut the breaks” on the immune response and keep it actively seeking out and killing cancer cells. Many patients fail on these treatments due to a lack of CD8+T cells, and other cytotoxic immune cells, being called into the tumor microenvironment. Many therapies exist to work in combination with checkpoint inhibitors to turn these immunologically “cold” tumors “hot” and prolong an immune response. I postulated that blocking PD-1, CD47, and SEMA4D in a novel triple combination treatment will allow for a greater presence of CD8+ T cells into the tumor microenvironment and double the overall response rate of patients. In a clinical trial consisting of 200 patients, half were placed into the control receiving Pembrolizumab (anti-PD-1) and TTI-621 (anti-CD47), while the experimental group received the triple treatment of Pembrolizumab, TTI-621, and Pepinemab (anti-SEMA4D). Results indicated that the triple combination treatment was effective in improving progression-free survival, overall survival, and overall response rate compared to that of the control. This clinical trial supports that this triple combination treatment can be potentially used as a cancer therapeutic in the future.

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