Phase 1 Study of Autologous Sirpα-Low Macrophages (SIRPant-M) Administered By Intratumoral Injection Alone or in Combination with External-Beam Radiotherapy in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma (NCT05967416)

Background and Significance. While a sentinel role of macrophages in channeling immune responses has long been recognized, the opportunity to harvest, harness and deploy macrophages for therapeutic potential has been underappreciated clinically. Most currently marketed and development-stage cell therapies target a single tumor-associated antigen, permitting activation of resistance and tumor escape mechanisms that frequently lead to relapse. High rates of CRS and neurotoxicity (ICANS) associated with CAR-T therapies complicate usage, with associated product labeling that includes a Risk Evaluation and Mitigation Strategy (REMS), mandating hospitalization and post-therapy monitoring with attendant administrative burden that precludes widespread use in community-based settings. Moreover, many subtypes of lymphoma (NHL) lack a readily druggable target. The current first-in-human Phase 1 study advances a novel paradigm in cell-therapy, deploying SIRPα-depleted activated macrophages, manufactured from an autologous mononuclear apheresis (SIRPant-M). In the context of macrophages, SIRPα acts as a strong negative regulator of (i) phagocytosis and (ii) productive pro-inflammatory T cell stimulation; therefore abrogation of SIRPα-activity serves as a necessary precondition for robust neo-antigen-specific anti-tumor responses. Requiring no genetic modification, in pre-clinical models these SIRPα-depleted macrophages orchestrated an immune response that targets multiple individual-specific and tumor-unique neo-antigens in parallel. SIRPant-M elicits a multi-pronged polyclonal immune response that transforms the tumor microenvironment (TME) by fostering a pro-inflammatory milieu that provides for unencumbered and orchestrated targeting of cancer cells via both cellular and humoral effector mechanisms. Manufactured and subsequently frozen as 3 aliquots from a single apheresis, activation of macrophages is brought about by conditioning the macrophages during ex vivo culture with a proprietary cytokine cocktail (PhagoAct™) with the added effect of modulating activity of SIRPα. This combination of product attributes permits the same cell product to have potential clinical applications in both solid tumor and hematologic malignancies. While this initial Phase 1 study administers the macrophages by intra-tumoral injection (ITI), subsequent studies aim to explore IV-dosing. Study design, methods and patients. This is a multicenter open-label Phase 1 study of SIRPant-M monotherapy, with sequential cohorts receiving low [90×10 6] and high [300×10 6] ITI cell doses. Cell product is administered alone or combined with focal external-beam radiotherapy (XRT). Each cell dose is administered in 3 ITI-fractions on days 1, 3, and 5 over 1 cycle. Upon confirmation of safety as a single agent, subsequent cohorts receive cell product concurrent with focally directed radiation in three 2.5 Gy fractions (7.5 Gy total). The primary end point, Dose Limiting Toxicity, is assessed over 30 days and dose escalation is gated by a standard 3+3 dose escalation design, overseen by a Safety Monitoring Committee. The enrollment target is 12-24 DLT-evaluable patients. The study enrolls an “all comers” B- and T-cell NHL population, including systemic and cutaneous histologies (CTCL), with relapsed or progressive disease following a minimum of 2- but no maximum number of prior therapies. Minimum age is 18, with no upper age limit. Prior CAR-T, bi-specific antibody and/or autologous/allogeneic transplant is allowed after recovery from treatment-related AEs. Patients must not receive immuno-suppression for GVHD and must have at least 1 target lesion that is 1.5 to 5 cm in diameter and accessible for safe ITI, ECOG ≤ 2, life expectancy > 3 months, renal/hepatic/coagulation parameters and blood counts that are standard for Phase 1 studies at baseline. Secondary and Exploratory Endpoints. Tumor response, including abscopal response, is evaluated by Lugano criteria or other Workgroup criteria as appropriate for the tumor type at the end of the DLT-period (Day 30), Week 12 and per SOC thereafter. Serial blood samples and a tumor biopsy before and 16 days after treatment are collected for multi-parameter analyte detection including pro-inflammatory cytokines, multiplex flow cytometry, scRNA sequencing, and ctDNA analysis to investigate pharmacodynamics and mechanism of action.