A Combination Therapy Strategy to Reverse Anti-PD-1 Therapy Resistance in Metastatic Ovarian Cancer Patients
Abstract
Most patients with advanced ovarian cancer (OC) relapse following surgery and platinum-based chemotherapy. Therefore, immune therapies have been tried as novel strategies for treatment of these patients. In immune therapy, emphasis is on changing patient’s own immune system in such a way that it recognizes and kills the tumor cells. Tumors try to hide from the immune cytotoxic T cells by expressing proteins on their surfaces that bind to the receptors on the T cells. These inhibitory proteins on tumor cells or their receptors on T cells are called checkpoints. After this binding, T cells are not able to get activated and become exhausted. Hence, the prevention of interaction between immune suppressive proteins on tumor cells with their respective receptors on T cells using checkpoint inhibitors can lead to activation of T cells, resulting in killing of tumor cells. One of the checkpoint inhibitors used is antibody to PD-1. This strategy has resulted in strong anti-tumor responses in millions of patients, yet in a significant number of patients with recurrent or persistent OC, monotherapy with anti-PD-1 resulted only in a very low rate of response. Recently, using mouse tumor models, we found the plausible reason for the resistance to anti-PD-1 therapy and a way to reverse this resistance. We found that treatment with anti-PD-1 given with a tumor-specific vaccine (that makes the T cells active) led to a delay in tumor growth and prolonged mouse survival. On the contrary, if anti-PD-1 were given before the vaccine, the anti-tumor effects were lost, meaning that scheduling of anti-PD-1 and vaccine are crucial for therapeutic outcomes. Interestingly, when anti-PD-1 was given before the vaccine, we found a significant increase in the number of a particular T cell subset in the tumors, which was identified as PD-1+CD38+ CD8+ T cells. We found that these cells were dysfunctional and dying. Interestingly, upon concomitant treatment with anti-PD-1 and vaccine, the numbers of these dysfunctional cells remained very low inside the tumors. To extend the applicability of these mice data in humans, we checked the number of these PD-1+CD38+CD8+ T cells in melanoma patients who either responded or did not respond to anti-PD-1 treatment. Interestingly, we found that, both in the tumors and in the blood of the non-responding patients, the number of these cells was higher than the responding patients both before and during the treatment. Since most human tumors tend to have suboptimal priming of the cytotoxic T cells that does not allow their proper activation, we speculate that anti-PD-1 treatment of suboptimally primed T cells leads to induction of PD-1+CD38+ CD8+ T dysfunctional cells, which can be reversed by optimum priming using tumor-specific vaccine given concomitant to anti-PD-1 treatment. Therefore, in this proposal, we hypothesized that, to improve the clinical outcome in patients with platinum-resistant OC, administration of a peptide vaccine before anti-PD-1 treatment is needed to reverse the resistance to anti-PD-1 therapy. We also hypothesized that the responding OC patients will have lower numbers of dysfunctional cells than the non-responding patients. To test these hypotheses, we propose a Phase II clinical trial with two aims. In the first aim, we will determine the efficacy of the treatment where a vaccine will be given before the anti-PD-1 therapy to the patients with metastatic platinum-resistant OC. In the second aim, we will evaluate the correlation of the dysfunctional cells with the response to the treatment. This Phase II trial will help in the development of a rational combination treatment using a peptide vaccine and anti-PD-1 therapy in platinum-resistant patients. We speculate that this treatment regimen would induce an optimized immune response against the OC, leading to strong therapeutic outcomes. This study will have immediate near-term impact on the clinical management of OC pati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010412
Entities
People
- Samir Khleif
Organizations
- Georgetown University
- United States Army