Treatment of patients with relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL) remains a major unmet medical need, with a five-year survival of only 21-39% in children and 20% in adults. Outcomes in B-Cell ALL (B-ALL) have improved, with several recently approved second-line therapies. In contrast, in the much smaller T-ALL population (~20% of ALL), nelarabine was the last new agent approved by FDA, in 2005, and few new therapies are in development. Fannin Partners, with its subsidiary, Allterum Therapeutics, is developing 4A10, a chimeric monoclonal antibody targeting the IL-7a receptor (CD127) developed by Dr. Scott Durum at the National Cancer Institute. The IL7R, critical to lymphocyte development, also plays an important role in the development and maintenance of T-ALL, including in relapsed disease. 4A10 binds the IL7R receptor, with an IgG1 Fc region that mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in addition to inhibiting IL-7 signaling. 4A10 has demonstrated robust anti-cancer activity against IL7R-expressing T-ALL in-vitro and in-vivo, including prolonged survival of mice with patient-derived T-ALL xenografts. Support from a Cancer Prevention and Research Institute of Texas (CPRIT) grant and seed financing, enabled our manufacturing scale-up and toxicological work, and we are now working towards submission of an IND. Further grant funding will enable us to conduct a first-in-human Phase 1 clinical trial to assess the safety and activity of 4A10 in T-ALL patients and assess pharmacodynamic and tumor biomarkers and correlate with 4A10 activity and tolerability in T-ALL patients. These specific aims will allow us (1) determine safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of 4A10 as monotherapy, (2) Determine the pharmacokinetic profile of 4A10 as monotherapy, (3) Assess the activity of 4A10 as monotherapy, (4) Explore potential pharmacodynamic markers of biologic and clinical activity and safety, (5) Explore correlation of tumor IL-7R expression with clinical activity, and (6) Explore correlation of cancer genetics with biologic and clinical activity and tolerability to 4A10. Completion of these aims will enable us to advance to a pivotal trial in patients with relapsed T-ALL, as well as other studies in additional ALL subpopulations and other IL7R-expressing cancers.
Public Health Relevance Statement: Project Narrative Children with relapsed T-cell acute lymphoblastic leukemia (T-ALL) have few options and a 5-year survival rate of only 30%, but, because there are so few patients (~200 patients/year), no new drugs have been developed for these patients in the last fifteen years. Fannin Partners is developing 4A10, a novel antibody against the IL-7 Receptor ?, that is a promising new therapy for these patients that was invented at the National Cancer Institute. This grant application will help support clinical trials of 4A10 in children with relapsed T-ALL.
Project Terms: TM-MKR; tumor biomarker; tumor specific biomarker; non-human primate; mutant; receptor; Pharmacodynamics; T-Cell Depletion; Rare Diseases; cross reactivity; drug development; cancer genetics; Adverse event; novel; experience; Maximum Tolerated Dose; Nelarabine; cell killing; Phase I Clinical Trials; After Care; After-Treatment; post treatment; pharmacodynamic biomarker; effector T cell; chimeric antigen receptor T cells; CAR T cell therapy; 0-11 years old; 21+ years old; Child Youth; Children (0-21); Adult Human; youngster; Cell Body; adulthood; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; autoimmune condition; autoimmune disorder; B blood cells; B cell; B cells; B-Cells; B-cell; Biologic Products; Biological Agent; biologics; experimental study; clinical development; Chemoresistance; Clinical Treatment Moab; mAbs; Ab-dependent cellular cytotoxicity; antibody dependent cell mediated cytotoxicity; antibody dependent cytotoxicity; antibody mediated cellular cytotoxicity; antibody-dependent cellular cytotoxicity; antibody-mediated cytotoxicity; Drosophila Homolog of NOTCH 1; NOTCH1; TAN1; Translocation-Associated NOTCH Homolog; clinical effect; Early-Stage Clinical Trials; Phase 1 Clinical Trials; CD127; CDW127; IL-7R alpha chain; IL-7R-alpha; IL-7Ralpha; IL-7Ra; IL7R; alpha chain interleukin-7 receptor; phase I protocol; first-in-human; early phase trial; Pediatric Leukemia; children with leukemia; leukemia in children; biopharmaceutical; biotherapeutic agent; Adverse Experience; Molecular Interaction; overexpression; Outcome; leukemia/lymphoma; next generation sequencing; FDA approved; anticancer activity; activity marker; Biological Markers; National Cancer Institute; Pediatric Oncology; design; tumor; New Agents; chemotherapy; manufacturing scale-up; novel therapeutics; Applications Grants; Grant; Adult; Aftercare; Maintenance; Antigen Targeting; in vivo; innovation; Population; Clinical Trials; Development; Play; Biological Products; In Vitro; Environment; IL7 gene; Biology; B-Lymphocytes; Mutation; Antibodies; Monoclonal Antibodies; antibody-dependent cell cytotoxicity; Pediatric Hospitals; Human; IgG1; Autoimmune Diseases; Mus; Signal Transduction; Role; Research Institute; Relapse; Safety; Work; Seeds; Interleukin 7 Receptor; Drug Kinetics; B-Cell Acute Lymphoblastic Leukemia; Malignant Neoplasms; T-Cell Leukemia; Acute T Cell Leukemia; Flow Cytometry; Cells; Lymphocyte; Patients; Child; first in man; developmental; overexpress; Testing; statistics; Tumor Markers; Texas; Survival Rate; T-Lymphocyte; Tissues; Immunophenotyping; Technology; Toxicology; cytokine; Mediating; NCI Organization; designing; Grant Proposals; pharmacodynamic marker; NGS Method; NGS system; next gen sequencing; nextgen sequencing; bio-markers; biologic marker; biomarker; novel therapy; new drug treatments; new drugs; Relapsed Disease; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; Oncology Cancer; innovative; lymphoma/leukemia; anti-cancer activity; experiment; experimental research; innovate; Heterograft; Heterologous Transplantation; Xenograft; Xenotransplantation; xeno-transplant; Normal Tissue; xeno-transplantation; Immunes; T-cell depletion therapy; T-lymphocyte depletion therapy; Orphan Disease; Rare Disorder; orphan disorder; Maximal Tolerated Dose; Maximally Tolerated Dose; Hematologic Cancer; Hematologic Malignancies; Hematological Malignancies; Hematological Neoplasms; Hematological Tumor; Hematopoietic Cancer; Malignant Hematologic Neoplasm; Receptor Protein; CD127 Antigens; IL-7 Receptors; IL7 Receptors; Interleukin 7 Receptor Alpha; biologic; Immunologic Subtyping; immunophenotype; Genetic Alteration; Signaling; Genetic Change; Genetic defect; biological signal transduction; Mice; genome mutation; Intracellular Communication and Signaling; Mice Mammals; Murine; Signal Transduction Systems; Cell Signaling; Modern Man; Children's Hospital; Cell Communication and Signaling; IL-7; IL-7 Gene; IL7; IL7 Protein; Interleukin 7 Precursor; Interleukin 7 Precursor Gene; Interleukin-7; Interleukin-7 Gene; Lymphopoietin-1; social role; Flow Cytofluorometries; Flow Cytofluorometry; Flow Microfluorimetry; Flow Microfluorometry; flow cytophotometry; Hematologic Neoplasms; Xenograft procedure; Titrations; Recurrent disease; Whole Blood; peripheral blood; cancer prevention; Lymphatic cell; Lymphocytic; Normal tissue morphology; lymph cell; Oncology; Pharmacokinetics; Acute B-Lymphocytic Leukemia; B cell progenitor acute lymphoblastic leukemia; B-ALL; B-Cell Acute Lymphocytic Leukemia; B-Cell Lymphoblastic Leukemia; B-cell ALL; B-cell precursor acute lymphoblastic leukemia; Pre-B-Cell Leukemia; Precursor B Lymphoblastic Leukemia; Plant Embryos; Plant Zygotes; seed; T-Cell Lymphocytic Leukemia; T-Lymphocytic Leukemia; Acute T-Cell Lymphoblastic Leukemia; Acute T-Cell Lymphocytic Leukemia; Acute T-Lymphocytic Leukemia; Precursor T Lymphoblastic Leukemia; T-Cell Type Acute Leukemia; T-lineage acute lymphoblastic leukemia; Funding; Teff cell; CAR T cells; CAR modified T cells; T cells for CAR; chimeric antigen receptor (CAR) T cells; chimeric antigen receptor modified T cells; CAR T therapy; chimeric antigen receptor (CAR) T cell therapy; chimeric antigen receptor T cell therapy; Therapeutic; Immune; Investigation; Medical; nonhuman primate; Measurement; Area; improved; Clinical; base; programs; Phase; Biological; Individual; chemoresistant; chemotherapy resistance; chemotherapy resistant; Binding; Dose; Childhood Leukemia; IL7R gene; NOTCH1 gene; T-Cells; thymus derived lymphocyte; Body Tissues
