Journal for immunotherapy of cancer · 2026
Antigen-IL-2 CAR-enhancer drives CAR-T fate and stemness, enhancing antitumor efficacy across models independent of IL-2Rα.
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Moravej Heydar, Rakhshandehroo Taha, Khan Radia M M, Rivet Victoria Marie, Marcandalli Elodie, Mantri Shreya R, Taklifi Pegah, Lee Uk-Jae, Louis Benjamin B V, Munaretto Leila A, Regan Kathryn, Farkash Zoe, Berland Lea, Gabr Zeina, Wolff Alexandra N, Kowalewski Antonia, Allen Harris H, Nili Ali, Baral Jessika, Mercadante Dayna, Fulciniti Mariateresa, Jacobson Caron A, Sperling Adam S, Nadeem Omar, Nia Hadi T, Hemann Michael, Munshi Nikhil C, Rashidian Mohammad
Аннотация
BACKGROUND: Limited durability of clinical responses remains a major challenge in chimeric antigen receptor (CAR)-T therapy. CAR-enhancers (CAR-Es), which fuse tumor antigens to interleukin (IL)-2 muteins, provide a targeted strategy to enhance CAR-T persistence and function. It remained unclear whether CAR-Es are effective across distinct tumor contexts, when using patient-derived T cells, or in preventing exhaustion and sustaining persistence. It was also unknown whether CAR-Es can selectively expand CAR-Ts in humanized mice with pre-existing T cells, and to what extent their efficacy depends on IL-2Rβγ vs IL-2Rα engagement. While IL-2Rα (CD25) has been classically linked to potent antitumor responses and memory formation, it also drives IL-2-associated toxicities, including vascular leak and preferential regulatory T cell expansion.
METHODS: We systematically dissected CAR-E signaling requirements by engineering IL-2 variants with selective receptor affinities. Multiple CAR-E constructs were developed and tested across a range of in vitro and in vivo models.
RESULTS: We demonstrate that CAR-E activity is entirely independent of IL-2Rα and critically dependent on IL-2Rβγ signaling. A next-generation IL-2Rα-sparing CAR-E maintained full potency, driving robust CAR-T expansion, persistence, and tumor clearance, even at low doses and when using CAR-T cells derived from previously treated multiple myeloma patients. These CAR-T cells not only resisted exhaustion but also re-expanded months later to eradicate tumor rechallenges. In humanized mice with pre-established T cells, CAR-Es selectively expanded CAR-Ts to dominate the circulating T-cell pool. CAR-E exerted a dominant influence on CAR-T fate, overriding tumor-derived cues and enforcing consistent phenotypes across diverse preclinical models.
CONCLUSIONS: These findings nominate a lead B-cell maturation antigen (BCMA)-IL-2 CAR-E candidate with strong translational potential for clinical development and establish IL-2Rβγ as a key driver of CAR-E activity. The results also identify IL-2Rα as dispensable and provide a mechanistic framework for designing safer, IL-2Rα-sparing CAR-Es.
METHODS: We systematically dissected CAR-E signaling requirements by engineering IL-2 variants with selective receptor affinities. Multiple CAR-E constructs were developed and tested across a range of in vitro and in vivo models.
RESULTS: We demonstrate that CAR-E activity is entirely independent of IL-2Rα and critically dependent on IL-2Rβγ signaling. A next-generation IL-2Rα-sparing CAR-E maintained full potency, driving robust CAR-T expansion, persistence, and tumor clearance, even at low doses and when using CAR-T cells derived from previously treated multiple myeloma patients. These CAR-T cells not only resisted exhaustion but also re-expanded months later to eradicate tumor rechallenges. In humanized mice with pre-established T cells, CAR-Es selectively expanded CAR-Ts to dominate the circulating T-cell pool. CAR-E exerted a dominant influence on CAR-T fate, overriding tumor-derived cues and enforcing consistent phenotypes across diverse preclinical models.
CONCLUSIONS: These findings nominate a lead B-cell maturation antigen (BCMA)-IL-2 CAR-E candidate with strong translational potential for clinical development and establish IL-2Rβγ as a key driver of CAR-E activity. The results also identify IL-2Rα as dispensable and provide a mechanistic framework for designing safer, IL-2Rα-sparing CAR-Es.