Immunomodulatory AVM0703 to bridge Relapsed/Refractory Diffuse Large B-Cell Lymphoma patients to CAR-T cell immunotherapy

PROJECT SUMMARY The approval of various Chimeric Antigen Receptor-T cells (CAR-T cells) for second- or third-line therapy has greatly expanded the treatment options available to patients with hematologic malignancies like Non-Hodgkin Lymphoma (NHL). However, not all NHL patients can benefit from this potentially life-saving treatment — 11- 15% of those with Diffuse Large B-Cell Lymphoma (DLBCL), the most common and aggressive NHL subtype, exhibit immune exhaustion markers linked to poor survival at initial diagnosis, and fewer than 20% of patients become eligible for second- or third-line CAR-T therapy. Even those who qualify for CAR-T cell therapy often experience CAR-T cell exhaustion, i.e. the inhibition of CAR-T cell proliferation and effector function resulting in resistance and relapse after CAR-T cell therapy. Also, inadequate disease control during the period between leukapheresis, CAR-T cell engineering, and infusion often results in the death of high-risk patients before they can receive CAR-T treatment. To prevent such deaths, and to provide alternatives for patients with no option for CAR-T or with CAR-T cell exhaustion, it is necessary to stabilize tumor burden in the interim period, for which bridging therapies (BT) such as steroids, chemotherapy, radiotherapy and targeted therapies are used. Unfortunately, current clinical evidence does not support the efficacy of existing BTs, and more effective ones are needed to improve patient outcomes and survival rates. To this end, AVM Biotechnology (AVM), a National Cancer Institute (NCI) 2023-24 showcase company, is developing a novel approach to BT using AVM0703, a proprietary high-concentration formulation of dexamethasone sodium phosphate (DSP). Unlike traditional corticosteroids, AVM0703, administered intravenously at supra-pharmacological doses, does not engage the glucocorticoid receptor, but mobilizes unique γδTCRinvTCR bispecific T and NKT cells (AVM-T/AVM-NKT), which infiltrate tumors and induce necrosis. AVM0703 is currently under clinical investigation in an adaptive design trial for relapsed/refractory (R/R) NHL patients who have no other approved treatment option and is also available for compassionate use under the FDA Expanded Access Program (EAP). Dose-escalation studies in Phase 1 trials showed that AVM0703 reduced immune exhaustion and improved blood counts, prompting us to pre-plan CAR-T following AVM0703 treatment. Therein, AVM0703 demonstrated no toxicity, while sparing key immune cells (monocytes, non-cancerous lymphocytes, platelets, RBCs, HSCs, and MSCs) and increasing neutrophils in 88% of NHL patients, indicating its ability to preserve innate immunity and reduce infection risk. Therefore, in this SBIR Phase II application, we propose adding a study arm to the current AVM0703 clinical trial (owing to the adaptive design) to further investigate the efficacy of AVM0703 as a bridging agent to potentially life-saving CAR-T therapy in R/R NHL DLBCL in order to design follow-on pivotal trials.