Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T-cells–a completed study overview

Abstract

We studied safety and proof of concept of a phase I/II trial with chimeric antigen receptor (CAR) T-cells in patients with metastatic renal cell carcinoma (mRCC). The CAR was based on the G250 mAb that recognized an epitope of carboxy-anhydrase-IX (CAIX). Twelve patients with CAIX+ mRCC were treated in three cohorts with a maximum of 10 daily infusions of 2×10(7) to 2×10(9) CAR T-cells. Circulating CAR T-cells were transiently detectable in all patients and maintained antigen-specific immune functions following their isolation post-treatment. Blood cytokine profiles mirrored CAR T-cell presence and in vivo activity. Unfortunately, patients developed anti-CAR T-cell antibodies and cellular immune responses. Moreover, CAR T-cell infusions induced liver enzyme disturbances reaching CTC grades 2-4, which necessitated cessation of treatment in four out of eight patients (cohort 1+2). Examination of liver biopsies revealed T-cell infiltration around bile ducts and CAIX expression on bile duct epithelium, adding to the notion of on-target toxicity. No such toxicities were observed in four patients that were pretreated with G250 mAb (cohort 3). The study was stopped due to the advent of competing treatments before reaching therapeutic or maximum tolerated dose in cohort 3. No clinical responses have been recorded. Despite that, from this trial numerous recommendations for future trials and their immune monitoring could be formulated, such as choice of the target antigen, format and immunogenicity of receptor and how the latter relates to peripheral T-cell persistence.

T Cell Maturation Stage Prior to and During GMP Processing Informs on CAR T Cell Expansion in Patients

“…In fact, the differentiation state of CD8 + T cells appeared to be inversely related to their capacity to proliferate and persist (10, 11). We have previously generated CAR T cells directed against carboxy-anhydrase-IX (CAIX) and treated patients with CAIX-positive metastatic renal cell carcinoma (mRCC) (12). Here, we assessed T cell maturation stage prior to and during CAR T cell expansion cultures, analyzed whether the T cell maturation stage affects CAR expression and function in vitro as well as the in vivo properties of CAR T cells, in particular expansion potential and absolute numbers of circulating CAR T cells.…”

Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives

“…Liver biopsies revealed CAR Tcell infiltration and CAIX expression on bile duct epithelium, consistent with off-target toxicity. No tumor response was recorded and the study was aborted [46][47][48].…”

Quantifying the Limits of Immunotherapies in Mice and Men

“…Target antigen may only be expressed by a subset of tumour cells and may not be sufficiently rare elsewhere in the body. For example, CAIX is expressed in some renal cell carcinomas, but it is also expressed in the liver bile duct resulting in on-target, off-tumour toxicities in a phase III trial [56]. Tumours may evolve to reduce expression of target antigen in response to successful T-cell killing, reducing the rate of tumour elimination or promoting outgrowth of therapy-resistant cells.…”