Improving the Durability of Immunological Memory During Anti-PD-1 Immunotherapy
Abstract
Immunotherapy using antibodies that block the PD-1 pathway has revolutionized treatment of metastatic melanoma with a subset of patients developing long-term durable control of their disease. This durable control likely rests, in part, on the capacity of memory immune cells, such as T cells, to surveil the body’s organs and the blood and then, upon re-encounter with the tumor, rapidly respond to kill the tumor cells. Maximizing the potential of these cells is therefore a desired goal of immunotherapy. Our project, Improving the durability of immunological memory during anti-PD-1 immunotherapy is an ambitious project that tackles the FY21 MRP Focus Area to delineate the immune response that influences metastatic spread and recurrence. Our studies in mouse models have shown that blocking PD-1 early during the course of infection impacts the development of a memory T cell population. Mice that lack the PD-1 protein clear influenza infection quickly but respond more slowly and kill virally infected cells more poorly after re-infection with a similar influenza strain. Likewise, in mouse tumor models early PD-1 blockade reduces antitumor immune responses upon re-encounter of tumor. Furthermore, there is significant heterogeneity within immune cell populations in mice or patients with tumors. Recent work has shown that anti-PD-1 therapy may expand only a portion of tumor-specific T cells. We believe anti-PD-1 therapy, therefore, influences both the generation of new memory immune responses and expansion and durability of pre-existing antitumor responses. To investigate these ideas, we have assembled the following human cohorts: (1) Cohort of patients with melanoma who are being treated with anti-PD-1 therapy and healthy subjects not on anti-PD-1 therapy. As it is challenging to differentiate between brand new antitumor responses or antitumor responses that are circulating at very low levels of detection, we are using vaccination against SARS-CoV-2 as a stand-in for tracking the development of brand new antitumor immune responses. We will track how the immune cells and antibody responses change over time and how this brand new immune response differs from pre-existing immune responses, such as prior responses to known melanoma-associated proteins – for patients with melanoma – or to common viruses after vaccination or natural infection. (2) Cohort of melanoma patients with stage III or stage IV disease who received anti-PD-1 as part of their therapy and with long-term clinical follow up. We can isolate and track the pre-existing immune responses in both the initial tumor sample and the peripheral blood to identify changes in gene expression in these cells over time. We will compare the heterogeneity of the T cell response both prior to the initiation of anti-PD-1 treatment and then over time in patients that develop a long-term durable response (over a year) compared to those that rapidly progress on anti-PD-1 therapy. All samples were generously donated and collected under the context of a clinical trial protocol approved by the appropriate Institutional Review Board. Tumor samples were collected at the time of surgery performed for clinical care. Blood draws for oncology patients were performed at the time that blood was being drawn for clinical treatment, so the overall risk is minimal to them. Although our studies center on patients with melanoma, we believe that this work has the potential to help all patients who receive anti-PD-1 therapy. During this grant’s funding cycle, this study will provide immediate insight into how patients treated with anti-PD-1 develop immunity after SARS-CoV-2 vaccination, which will contribute to our understanding of such questions as the need to boost further immunity during the ongoing pandemic. In the short- to medium-term, understanding how timing of anti-PD-1 therapy influences long-lived antitumor immune responses will have a significant impact on clinical t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211046
Entities
People
- Arlene Sharpe
Organizations
- Harvard University
- United States Army