Amph-Ligand Vaccine Enhances CAR-T Cell Activity against Solid Tumors

Chimeric antigen receptor-T (CAR-T) therapy specific to CD19 has shown clinical response in patients with B-cell malignancies. However, developing CAR-T therapy for solid tumors has been a challenge. To improve CAR-T efficacy in solid tumors, Ma and colleagues used a vaccination approach based on a recently developed method to link peptide antigens to albumin-binding phospholipid polymers. Binding of the amphiphile peptide (also called amph-ligand) to endogenous albumin enabled trafficking to the lymph nodes (LN), where it was inserted to the membrane of antigen-presenting cells (APC) and promoted activation and proliferation of CAR-T cells. First, fluorescein isothiocyanate (FITC)–conjugated peptide (amph-FITC) and anti-FITC CAR-T cells were used as a proof of concept to show the trafficking of amph-FITC to the draining LN, membrane binding, and proliferation of CAR-T cells in vivo. Blockade of a panel of costimulatory molecules expressed on APCs inhibited both proliferation and functional cytokine release of CAR-T cells in vivo. Next, a bona fide tumor antigen-specific CAR-T that targets EGFRvIII, in combination with amph-pepvIII (also called amph-vax) vaccination, was used in a tumor model of glioma cells expressing EGFRvIII. Treatment with EGFRvIII–CAR-T in combination with repeated amph-vax boosting significantly delayed tumor growth and prolonged survival, and surviving animals rejected tumor rechallenge. Rechallenge with parental cells that do not express EGFRvIII was also rejected, suggesting amph-vax activates endogenous T-cell responses against other tumor-derived antigens. Inclusion of both CD28 and 41BB domains further improved tumor control and increased survival when combined with amph-vax boosting. Lastly, a bispecific CAR platform was constructed by fusing anti–amph-ligand and a CAR targeting a tumor-derived antigen. Amph-ligand boosting improved the efficacy of the bispecific CAR-T cells in several models with low toxicity. Together, these results suggest a new vaccination approach to increase the efficacy of CAR-T cell therapy for solid tumors.

Ma L, Dichwalkar T, Chang JYH, Cossette B, Garafola D, Zhang AQ, et al. Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 2019;365:162–8.

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