Project 2: Treating metastatic lung cancer by targeting mutated KRAS with engineered T cells

Project Summary/Abstract – Project 2 Lung cancer of which ~85% are histologically non-small cell lung cancer (NSCLC) is still the leading cause of cancer deaths among men and women in the U.S. and worldwide. More than 50% of cases have distant rather than localized disease at diagnosis, with ~6% 5-year survival rate. The development of precision drugs that target mutated driver oncogenes has yielded high response rates, improved survival, and reduced toxicity compared to classical chemotherapy. However, virtually all patients develop drug resistance via mechanisms such as acquiring additional mutations in the oncogene target or activation of downstream signaling pathways. Immunotherapy is an orthogonal strategy for treating NSCLC. Immune checkpoint inhibition (ICI), initially approved for NSCLC in 2015, has provided therapeutic benefit by blocking inhibitory signals to activate immune responses in patients. However, responses are rarely durable and occur in only a minority of patients, with most responses lasting ~1 year. This reflects in part the specificity of the elicited T cell responses, which predominantly recognize non-truncal mutations not associated with oncogenicity, and failure of many tumors to attract and/or to actively block immune responses. An alternative immunologic strategy has been to generate and expand tumor-reactive T cells in vitro, and then infuse large numbers back into the patient. This approach has proven very effective in melanoma, and proof-of-principle studies have affirmed it is feasible in NSCLC. Our lab has been developing cell therapies for viral and malignant diseases for several decades, with a current focus on genetic engineering. Principles to reproducibly achieve tumor eradication have emerged, including targeting antigens essential to the tumor, providing durable T cell responses, and overcoming obstacles to T cell activity. We propose combining synthetic biology with cell engineering to address each of these obstacles. First, we will engineer both CD4 and CD8 T cells to function with the same Class I-restricted TCR and be specific for mutated KRAS, the most common oncogenic driver in NSCLC, thereby creating a coordinated CD4 and CD8 T cell response that can sustain anti-tumor activity. Second, we will use multi-omics technologies to generate high dimensional data sets describing events in the blood and at the tumor site to illuminate reasons for success and/or resistance. Third, we will develop next generation strategies to enhance efficacy by engineering T cells to express synthetic molecules that convert inhibitory and/or death signals to costimulatory and survival signals to promote durable T cell responses. The specific aims are: 1) Evaluate in a Phase I trial safety and activity/efficacy of autologous CD8 and CD4 T cells transduced to express an A11-restricted, high affinity, mKRASG12V-specific TCR and CD8ab chains in A11+ NSCLC patients. 2) Assess, using multiomics technologies, the immunobiology of the transferred T cells pre- and post- infusion and the impact the T cells have on the tumor as means to elucidate obstacles interfering with efficacy. 3) Evaluate next generation strategies for broadening and enhancing efficacy of T cell therapy in NSCLC.