Document text
Principal Investigator: Gianpietro Dotti
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $556,817
Funding agency: National Cancer Institute
ABSTRACT
Remarkable clinical responses have been reported in B-cell malignancies by adoptive transfer of T cells
redirected with a chimeric antigen receptor (CAR) specific for the CD19 antigen. However, developing CAR-Ts
for the treatment of solid tumors including ovarian cancer (OC) is challenging because: (1) OC-associated
antigens that are targetable by CAR-Ts are limited, generally not exclusively expressed by OC, and act as
passengers, not as drivers of tumorigenesis, allowing for antigenic drift; (2) OC tumor microenvironment (TME)
is highly immunosuppressive. In this proposal we aim at solving these critical issues. We have identified B7-H3
(CD276) as a suitable target for chimeric antigen receptor (CAR) T cells in OC. B7-H3 is a tumor-promoting
transmembrane protein aberrantly expressed in 60% to 93% of pancreatic cancer, melanoma, leukemia,
breast, prostate and OC, while limited expression is seen on normal healthy tissues. We have developed and
tested B7-H3.CAR-Ts in xenogeneic and immunocompetent tumor models showing antitumor activity is
several tumor models including OC and safety. Thus in Aim 1 we propose to conduct a phase I clinical study in
patients with OC to assess safety and antitumor activity of autologous B7-H3.CAR-Ts inoculated
intraperitoneally. An IND (IND19641) for this study has been obtained at University of North Carolina, and
clinical grade reagents to manufacture B7-H3.CAR-Ts are in hands. In Aim 2 we propose to conduct a
comprehensive immunologic analysis of tumor biopsies and ascites collected from patients enrolled in the
study before and after treatment to assess antigen loss and immunologic perturbation of the TME in OC. In
Aim 3, we propose to reprogram tumor-associated macrophages (TAMs) and myeloid derived suppressor cells
(MDSC) of the OC TME to a non-immunosuppressive state by using potent and orally bioavailable TAM RTK
small molecule inhibitors developed at University of North Carolina (IND128236). We will thus perform
preclinical studies to evaluate whether TAM RTK signaling inhibition in macrophages and MDSC would favor
the antitumor activity of B7-H3.CAR-Ts in a syngeneic model of OC. If successful, this strategy will be included
into a second phase of the proposed Phase I clinical study with B7-H3.CAR-Ts.
Terms: <Adoptive Cellular Immunotherapy><Adoptive Immunotherapy><Adult Folate Receptor 1><Adult Folate-Binding Protein><After Care><After-Treatment><Aftercare><Antigen Targeting><Antigens><Apoptotic><Ascites><Ascitic Fluid><Autologous><B Cell Antigen CD19><B blood cells><B cell><B cell malignancy><B cells><B lymphoid malignancy><B-Cells><B-Lymphocyte Antigen CD19><B-Lymphocyte Surface Antigen B4><B-Lymphocytes><B-cell><B7-H3><B7H3><Binding><Bioavailability><Biological Availability><Biopsy><Body Tissues><Breast Cancer><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CD19><CD19 Antigens><CD19 gene><CD19 molecule><CD276><CD276 gene><CTX><CYCLO-cell><Cancer Model><CancerModel><Carloxan><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Ciclofosfamida><Ciclofosfamide><Cicloxal><Clafen><Claphene><Clinical><Clinical Research><Clinical Study><Clinical Treatment Moab><Complex><Cross Reactions><Cycloblastin><Cycloblastine><Cyclophospham><Cyclophosphamide><Cyclophosphamidum><Cyclophosphan><Cyclophosphane><Cyclophosphanum><Cyclostin><Cyclostine><Cytophosphan><Cytophosphane><Cytoxan><Data><Development><Differentiation Antigen CD19><Dose><Early-Stage Clinical Trials><Electroporation><Endoxan><Endoxana><Enduxan><FOLR><FOLR1><FOLR1 gene><Family><Folate Receptor Alpha><Fosfaseron><Generalized Growth><Genoxal><Genuxal><Goals><Greater sac of peritoneum><Growth><Hand><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Heterograft><Heterologous Transplantation><Human><Immune><Immune Monitoring><Immune infiltrates><Immune mediated therapy><Immunes><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunologic Monitoring><Immunological><Immunological Monitoring><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomonitoring><Immunotherapy><Infusion><Infusion procedures><Integral Membrane Protein><Intracellular Communication and Signaling><Intratumoral heterogeneity><Intrinsic Membrane Protein><L-Serine><Ledoxina><Leu 12><Link><MOv18><Macrophage><Malignant Breast Neoplasm><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Melanoma><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Pancreatic Neoplasm><Malignant Tumor of the Ovary><Malignant Tumor of the Prostate><Malignant lymphoid neoplasm><Malignant neoplasm of ovary><Malignant neoplasm of pancreas><Malignant neoplasm of prostate><Malignant prostatic tumor><Melanoma><Messenger RNA><Mice><Mice Mammals><Mitoxan><Modeling><Modern Man><Modification><Molecular Interaction><Monitor><Monoclonal Antibodies><Murine><Mus><Myeloid-derived suppressor cells><Mφ><Neosar><Normal Tissue><Normal tissue morphology><North Carolina><Oncogenesis><Oral><Organ><Ovarian Cancer-Associated Antigen><Ovary Cancer><PD-1 blockade><PD1 blockade><PTK Receptors><Pancreas Cancer><Pancreatic Cancer><Patients><Peritoneal Cavity><Peritoneal Effusion><Peritoneal Fluid><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Physiologic Availability><Position><Positioning Attribute><Procedures><Procytox><Prognosis><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><Publishing><Reagent><Receptor Protein><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Recurrence><Recurrent><Refractory><Regulatory T-Lymphocyte><Relapse><Reporting><Safety><Sampling><Sendoxan><Serine><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Specificity><Syklofosfamid><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T cells for CAR><T-cell therapeutics><T-cell transfer therapy><Teff cell><Testing><Therapeutic><Tissue Growth><Tissues><Toxic effect><Toxicities><Transmembrane Protein><Transmembrane Protein Gene><Transmembrane Receptor Protein Tyrosine Kinase><Treg><Tumor Cell><Tumor Escape><Tumor Immune Escape><Tumor Promotion><Tumor-associated macrophages><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Universities><Woman><Xenograft><Xenograft procedure><Xenotransplantation><Zytoxan><abdominal dropsy><adoptive T cell transfer><adoptive T-cell therapy><adoptive cell immunotherapy><angiogenesis><anti-PD-1 blockade><anti-PD1 blockade><base><bases><biological signal transduction><cancer cell><cancer evasion><cancer immune escape><cancer immune evasion><cancer microenvironment><check point blockade><checkpoint blockade><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><clinical applicability><clinical application><clinical development><cross reactivity><developmental><effector T cell><electroporative delivery><exosome><fludarabine><gene electrotransfer><hands><heterogeneity in tumors><hydroperitonia><hydrops abdominis><immune cell infiltrate><immune check point blockade><immune checkpoint blockade><immune competent><immune microenvironment><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunosuppressive microenvironment><immunosuppressive myeloid cells><immunosuppressive tumor microenvironment><in vivo><infusions><inhibitor><innate immune function><intra-tumoral heterogeneity><intraperitoneal><intratumor heterogeneity><leukemia><lymphoid cancers><lymphoid malignancy><mAbs><mRNA><malignant breast tumor><manufacture><monoclonal Abs><mouse model><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><neoplastic cell><novel><ontogeny><ovarian cancer><pancreatic cancer model><pancreatic malignancy><pancreatic tumor model><participant enrollment><patient enrollment><peripheral blood><peritoneal dropsy><peritoneal exudate><phase I protocol><post treatment><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><programs><receptor><regulatory T-cells><response><safety assessment><small molecular inhibitor><small molecule inhibitor><success><suppressive myeloid cells><therapeutic T-cell platform><tumor><tumor evasion><tumor heterogeneity><tumor immune evasion><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions><tumorigenesis><tumorigenic><xeno-transplant><xeno-transplantation>