Cancer is one of the leading causes of death worldwide. Over the years, a number of conventional cytotoxic approaches for neoplastic diseases has been developed. However, due to their limited effectiveness in accordance with the heterogeneity of cancer cells, there is a constant search for therapeutic approaches with improved outcome, such as immunotherapy that utilizes and enhances the normal capacity of the patient's immune system. Of note, renal cell carcinoma and ovarian cancer are considered immunogenic, or "hot" cancers, in that tumors are infiltrated with T cells. This provides optimism that the immune system can be harnessed to be a potent and durable weapon against these cancers. Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement in personalized cancer treatment. In this strategy, a patient's own T cells are genetically engineered to express a synthetic receptor that binds a tumor antigen. We have developed a CAR T cell therapy, CM-CX1, designed to target a very specific marker (TIM-1) in renal and ovarian cancers. Expression of TIM-1 in healthy tissues is limited to absent. The goal of this Fast Track proposal is to finalize the preclinical work required for CM-CX1 filing of an IND for first-in-human evaluation.
Public Health Relevance Statement: NARRATIVE Much progress has been made in the dosing and scheduling optimization of conventional chemotherapy to maximize their effectiveness. Despite this, many solid tumors including ovarian and renal cell carcinomas, especially those diagnosed at advanced stages, progress and become refractory to treatment. Ovarian cancer and renal cell carcinomas are especially difficult cancers to treat in advanced stages as evidenced by a combined annual mortality of ~30,000 patients in the United States each year. We have developed and characterized a chimeric antigen receptor (CAR) T cell therapy that specifically targets tumor cells that express a novel target with high prevalence in clear cell carcinomas of the ovary and kidney but minimal/no expression in normal tissues.
Project Terms: Antibodies; Antigens; immunogen; Biological Assay; Assay; Bioassay; Biologic Assays; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Renal Cell Carcinoma; Grawitz Tumor; Hypernephroid Carcinoma; Hypernephroma; Nephroid Carcinoma; Renal Adenocarcinoma; Renal Cell Adenocarcinoma; Renal Cell Cancer; kidney adenocarcinoma; Cause of Death; Cells; Cell Body; Clinical Research; Clinical Study; Cryopreservation; Cryofixation; cold preservation; cold storage; Cessation of life; Death; Diagnosis; Disease; Disorder; Exhibits; Goals; Immune system; allergic/immunologic body system; allergic/immunologic organ system; Immunoglobulins; Immune Globulins; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; Killer Cells; K Cells; Lead; Pb element; heavy metal Pb; heavy metal lead; Lymphocyte; Lymphatic cell; Lymphocytic; lymph cell; mortality; Ovarian Carcinoma; Ovary Carcinoma; Legal patent; Patents; Patients; Production; Retroviridae; Retroviruses; Virus-Retrovirus; Risk; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Specificity; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Time; Tissues; Body Tissues; Tumor Antigens; Tumor-Associated Antigen; cancer antigens; tumor-specific antigen; United States; Virus; Work; cytokine; Schedule; antibody inhibitor; density; Organ; improved; Ovarian; Site; Clinical; Refractory; Phase; Evaluation; optimism; postiive attitude; Cell Surface Proteins; Technology Transfer; Solid Neoplasm; Solid Tumor; chemokine; Chemotactic Cytokines; Homologous Chemotactic Cytokines; Intercrines; SIS cytokines; chemoattractant cytokine; cell mediated therapies; cell-based therapeutic; cell-based therapy; cellular therapy; Cell Therapy; Therapeutic; Normal Tissue; Normal tissue morphology; Malignant Cell; cancer cell; weapons; Ovarian Clear Cell Cancer; Ovarian Clear Cell Carcinoma; Ovarian Clear Cell Neoplasm; Ovarian Clear Cell Tumor; Hematologic Cancer; Hematologic Malignancies; Hematological Malignancies; Hematological Neoplasms; Hematological Tumor; Hematopoietic Cancer; Malignant Hematologic Neoplasm; Hematologic Neoplasms; Investigation; Clinic; Infusion; Infusion procedures; Angiogenesis Antagonists; Angiogenesis Blockers; Angiogenetic Antagonists; Angiogenetic Inhibitors; Angiogenic Antagonists; Angiogenic Inhibitors; Angiostatic Agents; Anti-Angiogenetic Agents; Anti-Angiogenic Agents; Anti-Angiogenic Drugs; Antiangiogenesis Agents; Antiangiogenic Agents; Antiangiogenic Drugs; Neovascularization Inhibitors; antiangiogenic; Angiogenesis Inhibitors; experience; Tumor Cell; neoplastic cell; receptor bound; receptor binding; success; PBMC; Peripheral Blood Mononuclear Cell; cellular targeting; Toxicities; Toxic effect; CX1; glycoprotein CX 1; kidney injury molecule 1; renal KIM-1; rat KIM-1 protein; novel; Modality; Cell surface; Genitourinary Cancers; Urogenital Cancer; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; immunogenic; cell bank; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor of the Ovary; Ovary Cancer; ovarian cancer; Malignant neoplasm of ovary; Ideal 1; PTK Inhibitors; Protein Tyrosine Kinase Inhibitors; TK Inhibitors; Tyrosine Kinase Inhibitor; Effectiveness; ARHGEF5; GEF5; P60; TIM1; ARHGEF5 gene; Kidney Cancer; Kidney Carcinoma; Renal Cancer; Renal carcinoma; CD19; CD19 gene; Dose; cytotoxic; High Prevalence; immune-oncology; immuno oncology; immunology oncology; oncoimmunology; Immunooncology; MUC-1; MUC1; MUC1 gene product; Muc1 Mucin; Mucin 1; Mucin 1 protein; in vivo; Newly Diagnosed; Validation; Process; Development; developmental; neoplastic; pre-clinical; preclinical; design; designing; novel strategies; new approaches; novel approaches; novel strategy; manufacturing facility; Coupled; genetically modified cells; genetically engineered cells; chemotherapy; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; mouse model; murine model; tumor; candidate marker; candidate biomarker; effective therapy; effective treatment; Biological Markers; bio-markers; biologic marker; biomarker; phase 1 study; Phase I Study; chimeric antigen receptor; chimeric antigen T cell receptor; personalized cancer therapy; individualized cancer therapy; personalized cancer treatment; improved outcome; survival outcome; checkpoint therapy; check point immunotherapy; check point inhibitor therapy; check point inhibitory therapy; check point therapy; checkpoint immunotherapy; checkpoint inhibitor therapy; checkpoint inhibitory therapy; immune check point therapy; immune checkpoint therapy; cancer heterogeneity; preclinical development; pre-clinical development; Immune checkpoint inhibitor; Checkpoint inhibitor; immune check point inhibitor; Combination immunotherapy; combinatorial immunotherapy; dual immunotherapy; Clear cell renal cell carcinoma; ccRCC; first-in-human; first in man; side effect; chimeric antigen receptor T cells; CAR T cells; T cells for CAR; chimeric antigen receptor (CAR) T cells; CAR T cell therapy; CAR T therapy; chimeric antigen receptor (CAR) T cell therapy; chimeric antigen receptor T cell therapy; urogenital tract; genitourinary tract; Clear cell carcinoma; clear cell adenocarcinoma; Drug Side Effects
