Previously Funded Research

David Barbie, MD

Dana-Farber Cancer Insititute

Research Project:

Immune elimination of drug tolerant persister cells in oncogene-driven lung cancer

Summary:

Team Science Co-Awardees
Aaron Hata, MD, PhD, Massachusetts General Hospital
Eric Smith, MD, PhD, Dana-Farber Cancer Institute
Pasi Jänne, MD, PhD, Dana-Farber Cancer Institute
Shunsuke Kitajima, PhD, Japanese Foundation for Cancer Research

Lung cancer remains one of the deadliest cancers worldwide, particularly in its advanced stages. Metastatic non-small cell lung cancer (NSCLC) patients face poor prognoses despite recent advances in targeted therapies against EGFR, ALK, and KRAS mutations. These therapies, although initially effective, often lead to relapse driven by drug-tolerant persister (DTP) cells that develop resistance. Our research aims to tackle this critical challenge, focusing on innovative immune-based strategies to eradicate these persistent cells and improve patient outcomes.

Our project is aimed at exploiting vulnerabilities in DTP cells leveraging activating the innate immune programs and targeting of cell surface markers making them susceptible to immune attack. By leveraging our expertise in patient-derived models, targeted therapy, and immunotherapy, we propose a multi-faceted approach to target DTP cells, utilizing cutting-edge CAR T-cell therapy and modulation of the tumor microenvironment (TME).

Project 1: Co-opting innate immunity to eliminate drug tolerant persister cells
Project 1 aims to co-opt innate immunity by inhibiting TREX1, a negative regulator of STING-IFN signaling, to enhance immune response against DTP cells. Preliminary data suggest that TREX1 inhibition can unleash a potent antiviral response, making DTP cells vulnerable to immune attack. By targeting this pathway, we hope to stimulate a robust immune response capable of eliminating these resistant cells.

Project 2: Enhancing CAR T cells to eliminate drug tolerant persister cells
Project 2 focuses on enhancing CAR T cellular therapy to specifically target DTP cells in EGFR mutant NSCLC. While traditional CAR T therapies face challenges in solid tumors due to off-target toxicity and poor Tcell infiltration, our approach incorporates a novel strategies to address and overcome both these limitations.

Our research is poised to make significant strides in the treatment of metastatic NSCLC. The success of this project could rapidly translate into first-in-human clinical trials, offering new hope for patients who have exhausted other treatment options. Our group has a track record of working collaboratively, as well as translating discoveries from lab into clinical trials which have led to improved the lives of patients by offering more effective and less toxic therapies. By advancing our understanding and ability to combat DTP cells, we aspire to turn the tide against this resilient form of cancer and pave the way for more effective, long-lasting treatments for lung cancer patients.