Short title: RTX-240 phase 1 in solid tumorsA phase 1 trial of RTX-240, an allogeneic engineered red blood cell with cell -surface expression of 4-1BBL and trans-presented IL-15, in patients with advanced solid tumorsBackground: T cell checkpoint inhibition has revolutionized the treatment of cancer, however the key challenge in cancer immunotherapy is the development of resistant disease. Immune agonists and cytokines are promising approaches, but have shown limited success in the clinic. RTX-240 is an allogeneic cellular therapy genetically engineered to express high-copy numbers of trimeric 4-1BBL and IL-15/IL-15R fusion proteins on the cell surface. RTX-240 is designed to activate and expand CD8+ memory T cells and NK cells, and is restricted to the normal biodistribution of red blood cells to mitigate toxicity. Safety, pharmacodynamic (PD) effects, pharmacokinetics and preliminary efficacy of RTX-240 were assessed in a phase 1 study in patients (pts) with solid tumors. Methods: Pts with relapsed/refractory solid tumors not eligible for standard therapy were treated in dose escalating cohorts with RTX-240 Q4 or Q6W until disease progression or unacceptable toxicity. An exploratory cohort of IV and intratumoral (IT) dosing was enrolled (QW IV and IT x3 in cycle 1 and Q4W IV in subsequent cycles). Results: As of 11 Dec 2020, 14 pts (median age 55) were treated across 4 dose levels (1x108 to 1x1010 cells) administered IV or IV/IT. Pts had received a median of 3.5 therapies (range, 1-10); 10 pts had received prior PD-1/PD-L1 inhibitor therapy. Common tumor types include colorectal or other GI cancers (n=5) and melanoma (n=5). No patients experienced DLTs and no related grade (gr) >3 AE were observed. The most common related AE (gr 1-2) were fatigue (4 pts); chills, decreased appetite, arthralgia (3 pts each); and fever, myalgia, dysgeusia, nausea and hyperhidrosis (2 pts each). Additional irAE include gr 2 pneumonitis (n=1) and gr 1 elevated ALT/AST (n=1); the majority of irAE were observed in cycle 2 and beyond. RTX-240 was detected at the end of infusion sample in a dose dependent manner. Five pts (Q4W IV dosing) were evaluable for response by RECIST v1.1. A confirmed partial response (PR) was observed in 1 pt with anal cancer. Disease control, including stable disease or PR, occurred in 4/5 pts. PD studies in peripheral blood from all pts indicated increased numbers of NK cells in 12/14 pts (change from baseline, range 1.1-3 fold) and memory CD8+ T cells in 10/14 pts (change from baseline, range 1.2-3.3 fold). Activation of both NK and memory CD8+ T cells was observed by increased HLA-DR expression in 11/14 and 14/14 pts, respectively. Optional on-treatment biopsies are collected and preliminary data in one pt suggests infiltration of activated NK and T cells into the tumor microenvironment following dosing with RTX-240. Conclusions: RTX-240 is tolerable and leads to activation, expansion and trafficking of memory CD8+ T cells and NK cells, with preliminary evidence of anti-tumor activity. Exploration of the dose and schedule are ongoing in this study (NCT04372706).

Citation Format: Omid Hamid, Jason Luke, Alexander Spira, Geoffrey M. Kuesters, Iga Sienczylo, Gilad Gordon, Melissa L. Johnson. A phase 1 trial of RTX-240, an allogeneic engineered red blood cell with cell -surface expression of 4-1BBL and trans-presented IL-15, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT141.