The Thaxton Lab is working alongside Dr. David Neskey on his Phase II clinical trial studying the use of anti-PD-1 as a novel neoadjuvant presurgical therapy for locally advanced oral cavity cancer patients. We are studying ways to remodel metabolism to improve outcomes in this trial.
Prognosis and survival is poor in patients with OCC (11-13). We performed a clinical trial in which OCC patients received neoadjuvant immunotherapy prior to standard of care surgical resection of tumors. We administered three doses of q2weekly neoadjuvant a-PD-1 immunotherapy to block tumor-mediated inhibition of exhausted PD-1 CD8 TILs. After the third dose we used response evaluation criteria in solid tumors (RECIST) to assess patient responses. To date (n=11) ~36% of OCC patients experienced robust tumor regression, but ~64% of patients did not benefit from therapy (Fig. 1A-B). An emergent concept in immune oncology is that in vivo remodeling of CD8 TIL metabolism may improve patient responses to a-PD-1 therapy (14). Our group has found that protein translation in CD8 TILs is a metabolic property of antitumor T cells that is rapidly dismantled by the tumor microenvironment (6). We discovered that protein translation can be sustained by enriching mitoATP in CD8 T cells to support tumor control. Our data indicate that the energy sensor mTOR and glycoATP restrict CD8 T cell antitumor metabolism and translation. T cells in which mTOR was obstructed produced powerful antitumor immunity. The contribution of this work will be formal demonstration that inhibition of mTOR supports CD8 TIL antitumor metabolism and translation in OCC to improve response to a-PD-1 therapy. Successful completion of the aims will result in rapid implementation of mTOR inhibition to our neoadjuvant a-PD-1 therapy IIT in OCC patients.
Dr. Sophia Traven is currently developing a neoadjuvant immunotherapy clinical trial that aims to treat patients with high-grade soft tissue sarcoma in conjunction with standard of care radiotherapy and surgery
Clinical concept development
We are currently partnered with surgical and medical oncology to bring our novel combination therapy concept to sarcoma patients at MUSC. We aim to modulate metabolism within the sarcoma tumor microenvironment in order to invigorate TIL anti-tumor activity. Stay tuned!