SBIR-STTR Award

Despite treatment advances, the prognosis of adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and R/R diffuse large B-cell lymphoma (DLBCL) remains poor. Autologous T- cells modified to express a CD19-targeted chimeric antigen receptor (CAR T-cells) produce durable responses in subgroups of these patients, which has led to FDA approval of two such therapies to date; numerous other CAR T-cell therapies are under investigation, including a CD19-targeted CAR T-cell product bearing a CD28 costimulatory domain (19-28z) developed at Memorial Sloan Kettering Cancer Center. However, CAR T-cell therapy for B-ALL and DLBCL is associated with high risk of severe neurologic toxicity (including encephalopathy, dysphasia, seizures, and rarely, cerebral edema) and cytokine release syndrome (CRS). Host monocytes are the major source of elevated cytokines (IL-1, IL-6) observed in the context of neurologic toxicity. Administration of conditioning or “lymphodepleting” chemotherapy prior to CAR T-cell infusion, most commonly cyclophosphamide and fludarabine, appears to improve CAR T-cell expansion and efficacy by several mechanisms. However, a conditioning strategy that depletes monocytes as well as lymphocytes may reduce the risk of severe neurologic toxicity while preserving antitumor efficacy. The anti-CD45 antibody apamistamab labeled with 131-iodine (131-I apamistamab) is being investigated as myeloablative conditioning prior to hematopoietic cell transplantation in the Phase III SIERRA trial for patients with active, R/R acute myeloid leukemia. In SIERRA, transient lymphodepletion is observed clinically when 131-I apamistamab is given at low doses for dosimetry. Additionally, in preclinical models, a single low dose of 131-I-radiolabeled anti-CD45 antibody efficiently depletes lymphocytes, myeloid-derived suppressor cells, and regulatory T-cells, without impact on bone marrow hematopoietic stem cells. We propose investigating low-dose 131-I apamistamab in lieu of conditioning chemotherapy prior to 19-28z CAR T-cell therapy in patients with R/R B-ALL or R/R DLBCL, hypothesizing this will more effectively deplete host monocytes and reduce cerebrospinal fluid (CSF) levels of monocyte-derived cytokines, and thereby lower the incidence of severe neurologic toxicity following 19-28z CAR T-cell infusion. This clinical trial will be the first to test radiopharmaceutical conditioning prior to CAR T-cell therapy. The phase I/II study is designed to determine the maximum tolerated dose of 131-I apamistamab in this setting and subsequently to assess the incidence of severe neurologic toxicity associated with 131-I apamistamab conditioning and 19-28z CAR T-cell therapy in patients with R/R B-ALL or R/R DLBCL, as well as antitumor efficacy. A correlative study plan will characterize the effects of 131-I apamistamab on cytokine profiles in blood and CSF, and on the composition of the immune cellular microenvironment. Results of this trial can be applied toward ongoing development and refinement of CAR T-cell therapies targeting hematologic and non-hematologic malignancies.

Public Health Relevance Statement:
NARRATIVE Certain resistant forms of leukemia and lymphoma may be treated with a combination of chemotherapy and tumor-targeted immunotherapy made by modifying a patient’s own immune cells (CD19-targeted CAR T-cell therapy), but serious side effects including a spectrum of neurological toxicities known as ICANS and a serious inflammatory reaction known as CRS occur in a significant percentage of patients. White blood cells called monocytes secrete the signal molecules (cytokines) that initiate the inflammatory cascade leading to ICANS and CRS; therefore, giving a treatment to eliminate monocytes before CAR T-cell therapy (instead of chemotherapy) may decrease the risk of serious side effects. Actinium herein proposes a clinical trial, to be conducted at Memorial Sloan Kettering Cancer Center, evaluating the use of a radioisotope-linked antibody targeting monocytes and other immune cells (CD45-targeted antibody drug conjugate, iodine 131 [131-I] apamistamab), in place of chemotherapy, to help make CAR T-cell treatment safer and more effective for patients with resistant blood cancers.

Project Terms:
Actinium; Acute Myelocytic Leukemia; Address; Adopted; Adoptive Cell Transfers; Adult; aged; Antibodies; Antibody-drug conjugates; Autologous; B-Cell Acute Lymphoblastic Leukemia; Behavior Therapy; Biodistribution; Blood; Bone Marrow; cancer cell; CD19 Antigens; CD19 gene; CD28 gene; Cells; Cerebral Edema; Cerebrospinal Fluid; chemotherapy; chimeric antigen receptor; Clinical; Clinical Research; Clinical Trials; cohort; Combination Drug Therapy; conditioning; Correlative Study; Cyclophosphamide; cytokine; cytokine release syndrome; design; Development; Dose; dosimetry; Dysphasia; Effector Cell; Encephalopathies; Enrollment; experience; fludarabine; Generations; Hematology; Hematopoietic; hematopoietic cell transplantation; Hematopoietic Neoplasms; Hematopoietic stem cells; high risk; I131 isotope; Immune; immunoregulation; Immunotherapy; improved; In complete remission; Incidence; Inflammatory; Infusion procedures; Interleukin-1; Interleukin-6; Investigation; Kinetics; Label; large cell Diffuse non-Hodgkin's lymphoma; Lead; leukemia/lymphoma; Leukocytes; Link; Lymphocyte; Lymphocyte Count; Lymphoma cell; Maximum Tolerated Dose; Memorial Sloan-Kettering Cancer Center; monocyte; multimodality; Myeloid-derived suppressor cells; Myelosuppression; Neurologic; Neurotoxicity Syndromes; Non-Hematologic Malignancy; novel strategies; outcome forecast; patient population; patient subsets; Patients; Peripheral; peripheral blood; Phase; Pre-Clinical Model; preclinical study; preservation; Prior Chemotherapy; PTPRC gene; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reaction; Recovery; Refractory; Regimen; Regulatory T-Lymphocyte; Relapse; Reporting; Resistance; response; Risk; Safety; safety and feasibility; Seizures; side effect; Signaling Molecule; Source; Structure; T cell therapy; T-Lymphocyte; targeted treatment; Testing; Therapeutic; Toxic effect; Transplantation Conditioning; tumor

Despite treatment advances, the prognosis of adult patients with relapsed or refractory (R/R) B-cell acutelymphoblastic leukemia (B-ALL) and R/R diffuse large B-cell lymphoma (DLBCL) remains poor. Autologous T-cells modified to express a CD19-targeted chimeric antigen receptor (CAR T-cells) produce durable responsesin subgroups of these patients, which has led to FDA approval of two such therapies to date; numerous otherCAR T-cell therapies are under investigation, including a CD19-targeted CAR T-cell product bearing a CD28costimulatory domain (19-28z) developed at Memorial Sloan Kettering Cancer Center. However, CAR T-celltherapy for B-ALL and DLBCL is associated with high risk of severe neurologic toxicity (includingencephalopathy, dysphasia, seizures, and rarely, cerebral edema) and cytokine release syndrome (CRS). Hostmonocytes are the major source of elevated cytokines (IL-1, IL-6) observed in the context of neurologic toxicity.Administration of conditioning or "lymphodepleting" chemotherapy prior to CAR T-cell infusion, most commonlycyclophosphamide and fludarabine, appears to improve CAR T-cell expansion and efficacy by severalmechanisms. However, a conditioning strategy that depletes monocytes as well as lymphocytes may reduce therisk of severe neurologic toxicity while preserving antitumor efficacy. The anti-CD45 antibody apamistamablabeled with 131-iodine (131-I apamistamab) is being investigated as myeloablative conditioning prior tohematopoietic cell transplantation in the Phase III SIERRA trial for patients with active, R/R acute myeloidleukemia. In SIERRA, transient lymphodepletion is observed clinically when 131-I apamistamab is given at lowdoses for dosimetry. Additionally, in preclinical models, a single low dose of 131-I-radiolabeled anti-CD45antibody efficiently depletes lymphocytes, myeloid-derived suppressor cells, and regulatory T-cells, withoutimpact on bone marrow hematopoietic stem cells.We propose investigating low-dose 131-I apamistamab in lieu of conditioning chemotherapy prior to 19-28z CART-cell therapy in patients with R/R B-ALL or R/R DLBCL, hypothesizing this will more effectively deplete hostmonocytes and reduce cerebrospinal fluid (CSF) levels of monocyte-derived cytokines, and thereby lower theincidence of severe neurologic toxicity following 19-28z CAR T-cell infusion. This clinical trial will be the first totest radiopharmaceutical conditioning prior to CAR T-cell therapy. The phase I/II study is designed to determinethe maximum tolerated dose of 131-I apamistamab in this setting and subsequently to assess the incidence ofsevere neurologic toxicity associated with 131-I apamistamab conditioning and 19-28z CAR T-cell therapy inpatients with R/R B-ALL or R/R DLBCL, as well as antitumor efficacy. A correlative study plan will characterizethe effects of 131-I apamistamab on cytokine profiles in blood and CSF, and on the composition of the immunecellular microenvironment. Results of this trial can be applied toward ongoing development and refinement ofCAR T-cell therapies targeting hematologic and non-hematologic malignancies.

Public Health Relevance Statement:
NARRATIVE Certain resistant forms of leukemia and lymphoma may be treated with a combination of chemotherapy and tumor-targeted immunotherapy made by modifying a patient's own immune cells (CD19-targeted CAR T-cell therapy), but serious side effects including a spectrum of neurological toxicities known as ICANS and a serious inflammatory reaction known as CRS occur in a significant percentage of patients. White blood cells called monocytes secrete the signal molecules (cytokines) that initiate the inflammatory cascade leading to ICANS and CRS; therefore, giving a treatment to eliminate monocytes before CAR T-cell therapy (instead of chemotherapy) may decrease the risk of serious side effects. Actinium herein proposes a clinical trial, to be conducted at Memorial Sloan Kettering Cancer Center, evaluating the use of a radioisotope-linked antibody targeting monocytes and other immune cells (CD45-targeted antibody drug conjugate, iodine 131 [131-I] apamistamab), in place of chemotherapy, to help make CAR T-cell treatment safer and more effective for patients with resistant blood cancers.

Project Terms:
<21+ years old><131 Iodine>