A long-acting form of Interleukin-7 improves CAR T cell activity

Chimeric antigen receptor (CAR) T cell therapy has been successfully used for treating relapsed or refractory B cell cancers. However, in some patients, suboptimal CAR T cell efficacy allows antigen-positive tumor cells to evade destruction by the immune system. This limited efficacy is thought to be due to inherent immune deficiencies, including T cell defects, that restrict the expansion and persistence of CAR T cells in vivo. For this reason, promoting T cell growth and survival is a promising therapeutic strategy to improve patient outcomes. To test this hypothesis, researchers at Washington University in St. Louis investigated the impact of administering CAR T cell therapy with a long-acting form of Interleukin-7 (IL-7). Their findings, published in Nature Communications, showed this approach to enhance CAR T cell efficacy, resulting in the lasting survival of CD19+ tumor-bearing mice.

rhIL-7-hyFc enhances CAR T cell expansion and maintains functionality in vitro

Extending the serum half-life of IL-7 through fusion to the Fc region of human IgG (rhIL-7-hyFc) has demonstrated increased CD4+ and CD8+ T cell counts in a human clinical trial. To test the effects of rhIL-7-hyFc on CAR T cells in vitro, Kim et al. generated human TCR-deficient anti-CD19 CAR T cells (UCART19) by electroporating activated donor T cells with Cas9 mRNA and a TRAC-targeted gRNA (both supplied by TriLink) before transduction with an anti-CD19 CAR lentiviral vector. The UCART19 cells were then cultured with rhIL-7-hyFc in the presence of CD19+ tumor cells and monitored for proliferation and cytokine expression. Compared with the vehicle-treated control, which failed to proliferate over the course of the assay, rhIL-7-hyFc led to robust expansion of UCART19 cells, with an IsoLite IsoCode assay showing these to exhibit CAR T functionality.

rhIL-7-hyFc prolongs the survival of CD19+ tumor-bearing mice

To determine whether rhIL-7-hyFc would promote in vivo expansion of UCART19 and improve anti-tumor efficacy, Kim et al. injected immunodeficient (NSG) mice with reporter-expressing CD19+ tumor cells before treating them with UCART19 cells and rhIL-7-hyFc. While the murine cohort that received only UCART19 died within 30 days, those treated with UCART19 and rhIL-7-hyFc were alive beyond 80 days, with no clinical signs of xenogeneic graft versus host disease (GVHD). In addition, the rhIL-7-hyFc-treated mice showed a four log-fold expansion of UCART19 compared with the vehicle-treated animals, with bioluminescent imaging revealing minimal signal from the CD19+ tumor cells.

 

A promising clinical adjuvant

Kim et al. performed several other studies to assess the clinical utility of rhIL-7-hyFc further. These include using a myeloid-targeting CAR T (UCART33) in an NSG mouse model of acute myeloid leukemia. From these data, researchers confirmed that the effects of rhIL-7-hyFc on CAR T cells were not solely limited to UCART19 and treating C57BL/6 mice with murine CD19-targeting CAR T cells (mCART19) and rhIL-7-hyFc showed rhIL-7-hyFc to prolong CAR T cell persistence in the immunocompetent host without causing undue toxicity. Therefore, rhIL-7-hyFc is a promising clinical adjuvant to enhance CAR T cell activity and improve outcomes for patients with B cell malignancies.

 

Featured products: TRAC gRNA, spCas9 mRNA

Article reference: Kim MY, Jayasinghe R, Devenport JM, et al., A long-acting interleukin-7, rhIL-7-hyFc, enhances CAR T cell expansion, persistence, and anti-tumor activity, Nat Commun. 2022;13(1):3296.

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