CAR T cells for infection, autoimmunity and allotransplantation

Abstract

Chimeric antigen receptors (CARs) have shown remarkable ability to re-direct T cells to target CD19-expressing tumours, resulting in remission rates of up to 90% in individuals with paediatric acute lymphoblastic lymphoma. Lessons learned from these clinical trials of adoptive T cell therapy for cancer, as well as investments made in manufacturing T cells at commercial scale, have inspired researchers to develop CARs for additional applications. Here, we explore the challenges and opportunities of using this technology to target infectious diseases such as with HIV and undesired immune responses such as autoimmunity and transplant rejection. Despite substantial obstacles, the potential of CAR T cells to enable cures for a wide array of disease settings could be transformational for the medical field.

Figure 1.. CD4-based chimeric antigen receptors (CARs) for HIV-1.

Extracellular antigen recognition domains of CARs determine their specificity for HIV-1 by targeting different regions of the HIV envelope protein (Env). a | The full-length extracellular domain of CD4 is comprised of four domains. Domains 1 and 2 are crucial for binding to the HIV gp120 component of the Env trimer. b | CARs containing broadly neutralizing antibody (bNab)-derived single chain variable fragments (scFVs) have been produced from antibodies such as VRCO1 and PG9, which differentially bind the Env trimer at the CD4-binding site and second variable (V2) loop, respectively. c, d | Bi-specific CARs confer dual specificity for HIV through the CD4–gp120 Env interaction, and either binding of the scFV to an alternative region in Env or binding of the carbohydrate recognition domain (CRD) of a C-type lectin to glycan motifs on Env.

Figure 2.. Engineering CAR T cells to traffic to B cell follicles.

The trafficking of chimeric antigen receptor (CAR)-expressing T cells into the B cell follicles of lymphoid tissue could facilitate the elimination of CD4⁺ T follicular helper (TFH) cells persistently infected with HIV-1. Naturally occurring HIV-specific CD8⁺ cytotoxic T lymphocytes (CTLs) are present in the extrafollicular region of a lymph node. However, many CTLs fail to access the B cell follicle because they lack expression of the follicular homing receptor CXC-chemokine receptor 5 (CXCR5), which can mediate chemotaxis along a CXC-chemokine ligand 13 (CXCL13) concentration gradient. However, CXCR5 gene engineering could enable HIV-specific CAR T cells to enter into the B cell follicle. Upon entry, CAR T cells could eliminate infected CD4⁺ TFH cells and reduce the population size of cells that contribute to recrudescent viraemia after interruption of combination antiretroviral therapy (cART). In addition, before cART interruption, administration of latency-reversing agents, such as an IL-15 superagonist complex, could synergize with CAR T cells to eliminate the pool of infected CD4⁺ T cells that exist in lymphoid and peripheral tissues.