Phase 1, open-label clinical trial to treat stage IV cancer patients harboring multiple patient-specific mutated cell surface proteins with chimeric antibodies.

Abstract

TPS2672 Background: Despite the advent of multiple classes of systemic cancer treatments, tumor recurrence and subsequent resistance to systemic therapy remain a persistent challenge. Thus, newer treatment strategies are needed for metastatic cancer refractory to extant therapies. Leveraging the vast landscape of targetable tumor-specific mutated peptides (TSPs) on the surface of malignant cells offers an opportunity for individualized antibody therapy. These surface TSPs arise due to genetic instability and progressive accumulation of random missense mutations in cancer cells, resulting in dozens to hundreds of substituted amino acids in proteins at the cancer cell surface. We refer to surface proteins harboring substituted amino acids as Mutated cell Surface Proteins (MSPs). Antibodies generated against short TSPs preferentially bind to the mutated peptide compared to the nonmutated peptide. Notably, most cancers harbor several distinct MSPs. For instance, of 100 colon cancer cases, 96% harbored ≥10 MSPs, with similar findings in lung cancer (97%), melanoma (93%), lymphoma (92%), bladder cancer (85%), and stomach cancer (84%). While the presence of many MSPs is common, each patient harbors a unique set of MSPs. Study sponsor has developed a means of preparing custom antibodies against the TSPs present in multiple MSPs to inhibit cancer growth in several preclinical models, prompting a pan-tumor Phase I study evaluating the safety and feasibility of such therapy in refractory cancer patients. Methods: This is a phase I first-in-human study aiming to enroll up to 12 eligible subjects. Primary objective: Safety and tolerability. Secondary objectives: Feasibility of producing and administering the protocol-directed treatment to the patient population; progression-free survival; response rate. Key Inclusion Criteria: a) Stage IV refractory cancer (breast, colon, esophageal, kidney, lung, ovarian, bladder urothelial, stomach, or pancreatic cancers, melanoma, or lymphoma); b) availability of tumor and matched normal tissue sequence data. Treatment: Custom-manufactured chimeric antibodies are being used to target a minimum of 2 to 8 MSPs per patient. An interval of 4- to 6-month antibody production interval is required from initial consent to the start of treatment. The dose-limiting toxicity (DLT) period is 4 weeks; thereafter, in addition to antibody treatment, subjects can receive standard of care [immunotherapy, targeted therapy or hormonal therapies]. Treatment schedule: Week 1, 100 mg i.v.; week 2, 200 mg i.v.; week 3 400 mg; and then 400 mg i.v. every other week for total of 10 doses. We have enrolled 3 subjects and have completed treatment of Subject #1 (bladder cancer), with no DLT to date. The study is ongoing since 12/2025. Clinical trial information: NCT06674538 .