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A CAR enhancer increases the activity and persistence of CAR T cells.

Taha RakhshandehrooShreya R MantriHeydar MoravejBenjamin B V LouisAli Salehi FaridLeila MunarettoKathryn ReganRadia M M KhanAlexandra WolffZoe FarkashMin CongAdrien KuhnastAli NiliUk-Jae LeeHarris H AllenLea BerlandEster SimkovaSafak C UsluSoheil TavakolpourJennifer E RowleyElisabeth CodetHaneyeh ShahbazianJessika BaralJason PyrdolCaron A JacobsonOmar NadeemHadi T NiaKai W WucherpfennigMohammad Rashidian
Published in: Nature biotechnology (2024)
Although chimeric antigen receptor (CAR) T cell therapies have demonstrated promising clinical outcomes, durable remissions remain limited. To extend the efficacy of CAR T cells, we develop a CAR enhancer (CAR-E), comprising a CAR T cell antigen fused to an immunomodulatory molecule. Here we demonstrate this strategy using B cell maturation antigen (BCMA) CAR T cells for the treatment of multiple myeloma, with a CAR-E consisting of the BCMA fused to a low-affinity interleukin 2 (IL-2). This selectively induces IL-2 signaling in CAR T cells upon antigen-CAR binding, enhancing T cell activation and antitumor activity while reducing IL-2-associated toxicities. We show that the BCMA CAR-E selectively binds CAR T cells and increases CAR T cell proliferation, clearance of tumor cells and development of memory CAR T cells. The memory cells retain the ability to re-expand upon restimulation, effectively controlling tumor growth upon rechallenge. Mechanistic studies reveal the involvement of both CAR and IL-2 receptor endodomains in the CAR-E mechanism of action. The CAR-E approach avoids the need for specific engineering and enables CAR T cell therapy with lower cell doses.
Keyphrases
  • cell therapy
  • cell proliferation
  • induced apoptosis
  • stem cells
  • oxidative stress
  • mesenchymal stem cells
  • working memory
  • cell cycle
  • dna methylation
  • endoplasmic reticulum stress