Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer

Abstract

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity.

Systematic testing and specificity mapping of alloantigen-specific chimeric antigen receptors in T regulatory cells

“…Mouse-derived CARs can be highly effective, but T cells expressing humanized or fully human CARs have increased cell persistence and efficacy (40), and decreased side effects (17,(19)(20)(21)(22)41). To date, there has been no comprehensive investigation of the applicability of bioinformatic methods for humanizing mAbs for use in CAR constructs.…”

“…CARs classically contain a single chain of antibody variable domains (scFv) derived from heavy and light chains of well-characterized, high-affinity mAbs, which face the extracellular space (12). CARs derived from mouse scFvs can be highly effective (13)(14)(15)(16) but carry the risk of immunogenicity, with sensitization possibly limiting therapeutic efficacy and repeat dosing (17)(18)(19)(20)(21)(22)(23). Therapeutic mAb studies have Chimeric antigen receptor (CAR) technology can be used to engineer the antigen specificity of regulatory T cells (Tregs) and improve their potency as an adoptive cell therapy in multiple disease models.…”

Co-expression of IL-7 and PH20 Promote anti-GPC3 CAR-T Tumor Suppressor Activity in Vivo and in Vitro

“…CAR-T targeting the B-cell maturation antigen (BCMA) has also shown positive therapeutic effects in clinical trials [5][6][7]. However, CAR-T cell therapy has not yet had similar results in solid tumors [8][9][10]. Solid tumors have a more complex immunosuppressive microenvironment and there are many immunosuppressive cells and cytokines which inhibit the activation and survival of CAR-T cells within the tumor [11,12].…”

IL‐18R‐dependent and independent pathways account for IL‐18‐enhanced antitumor ability of CAR‐T cells

“…[3][4][5][6] Various strategies have been employed to enhance the function of CAR-T cells for use in cancer immunotherapy. [3][4][5][6] Various strategies have been employed to enhance the function of CAR-T cells for use in cancer immunotherapy.…”