R01CA260902

Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor-Alpha Redirected CAR T Cells for Ovarian Cancer - Abstract

Applying CAR T cell therapy to solid tumors such as ovarian cancer (OVCA) is widely considered a major opportunity but also a major challenge and thus the focus of this proposal.

Here, we seek to develop new clinical strategies for OVCA and other solid tumors using CAR T cells specific for folate receptor-alpha (FRA), as the target of next-generation CAR T cell therapy. FRA is a surface protein that is expressed in 80-90% of OVCA cases and associated with poor prognosis. FRA is known to be a safe, "druggable" therapeutic target in trials of antibody-drug conjugates and bispecific antibody armed T cells in platinum-resistant OVCA patients, with clinical response rates of 26% and 27%, respectively. These agents are short-lived in patients and thus responses are non-enduring; CAR T cells, however, have the capacity for persistence and maintained activity in vivo.

In multiple preclinical models, human FRA CAR T cells exhibit potent anti-tumor efficacy against human solid tumor xenografts that express FRA.

Here, we propose to test the central hypothesis that lentivirus-engineered FRA-specific CAR T cells can achieve clinically meaningful tumor responses in patients with recurrent OVCA without untoward toxicity. We propose to:

(1) Determine the feasibility, safety, and tumor response following intraperitoneal injection of autologous FRA lentivirus CAR T cells in patients with confirmed FRA-overexpressing recurrent OVCA in a Phase I dose escalation trial (NCT03585764).

(2) Determine FRA CAR persistence, immunological potency, and mechanism of FRA-specific CAR T cell activity in treated patients to understand the immune reaction and other modulations in the OVCA microenvironment following CAR T cell injection.

(3) Determine the scope, breadth, and duration of induced systemic immune responses, as a foundation for anticipated future combinatorial therapies.

In this line, a secondary hypothesis is that schedule-dependent preconditioning of the tumor microenvironment (TME) is a requirement for effective therapy. In OVCA and other cancers, tumor-associated macrophage (TAM) accumulation is associated with poor outcome and resistance to immunotherapy, suggesting that TAM depletion or disruption may improve patient outcome.

We have now developed novel CAR T cell technology that mediates deep and highly selective depletion of immunosuppressive M2-like TAMs. In preclinical studies, we find that anti-TAM CAR T cells augment endogenous CD8+ T cell antitumor responses, spare M1-like macrophages, re-educate the TME, and inhibit tumor progression in vivo in three independent mouse tumor models, suggesting that synergy with FRA CAR T cell therapy may be achieved, particularly when applied as a preparative preconditioning regimen.

We are positioned to test this novel hypothesis by evaluating and optimizing this novel TAM depletion regimen, and other established approaches, in the context of FRA CAR T cell therapy in various preclinical tumor models, allowing us to capitalize on the discovery of a novel effective combination as a bridge to next-generation clinical trials for patients with OVCA and solid tumors bearing TAM accumulation.

Trustees Of The University Of Pennsylvania

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]

Philadelphia, Pennsylvania 191045167 United States

Single Zip Code

National Cancer Institute's Investigator-Initiated Early Phase Clinical Trials for Cancer Treatment and Diagnosis (R01 Clinical Trial Required) (PAR-21-033)

Amendment Since initial award the End Date has been extended from 03/31/27 to 08/31/27 and the total obligations have increased 383% from $672,991 to $3,252,105.