U01CA256801

Optimizing Dual-Targeted and Dual-Armored CAR T Cells for Small Cell Lung Cancer - Abstract

A patient's own T cells can be modified using gene therapy technology to express receptors, termed chimeric antigen receptors or CARs, which allow these immune T cells to recognize proteins on the tumor cell surface. In turn, these CAR-modified T cells can recognize and kill the patient's own tumor cells. This approach has been successful in some hematological malignancies. However, it has not been successful to date in solid tumors, including small cell lung cancer (SCLC).

Two mechanisms by which SCLC may evade T cell-mediated killing are loss of expression of antigens and suppression of T cell function in the tumor microenvironment. In this proposal, we will attempt to overcome these barriers by designing CAR T cells that target two SCLC antigens simultaneously and produce multiple factors ("armors") that enhance T cell activity in solid tumors. We hypothesize that these dual-armored, dual-targeted (DADT) CAR T cells will be more effective against SCLC than previous T cell-mediated and immune therapies.

We have previously shown that CAR T cells targeted to either the antigen GD3 or to the antigen DLL3, both of which are expressed on the majority of small cell lung cancers, are capable of killing SCLC cells in preclinical systems. Additionally, we have developed multiple armored CAR T cells that secrete factors such as IL-18 or an antibody-derived single-chain variable fragment (scFv) that blocks the immune checkpoint receptor PD-1, or an scFv blocking the phagocytosis-inhibitory signal CD47 on tumor cells. All of these armors enhance CAR T cell activity in our in vivo model systems through different mechanisms.

In Aim 1 of this proposal, we will generate CAR T cells targeting DLL3 and GD3 simultaneously to overcome antigen heterogeneity and antigen loss in tumors as a means of escape from T cell-mediated killing. Simultaneously, in Aim 2, we will test pairs of armors to identify the pair that is the most effective at enhancing the activity of single antigen-targeted CAR T cells against SCLC in vivo in immunocompetent systems. We will then analyze the immune cells in the SCLC tumor microenvironment following CAR T cell treatment to assess changes mediated by the armored CAR T cells.

Ultimately, in Aim 3, we will combine these approaches to generate CAR T cells that recognize GD3 and DLL3 and produce multiple armors. These DADT CAR T cells for SCLC may be suitable for further preclinical testing in preparation for clinical trials beyond the scope of this proposal, representing a novel therapeutic approach to SCLC. Given our robust track record in CAR T cell clinical translation, we fully anticipate having new CAR T cells suitable for clinical trials at the conclusion of funding.

Additionally, these novel CAR T cells may be used as tools to explore the interactions between T cells and the SCLC microenvironment. The analysis of changes in SCLC tumors induced by the armored CAR T cells proposed here may reveal novel aspects of SCLC biology and illuminate mechanisms of immune escape and treatment failure in SCLC.

Health Research

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Buffalo, New York 14263 United States

Single Zip Code

Small-Cell Lung Cancer (SCLC) Consortium: Therapeutic Development and Mechanisms of Resistance (U01 Clinical Trial Not Allowed) (PAR-19-361)

Amendment Since initial award the End Date has been extended from 03/31/26 to 03/31/27 and the total obligations have increased 391% from $661,095 to $3,246,184.