Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T-cells-a completed study overview.
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.
Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Cancer Institute, 3015 CN Rotterdam, The Netherlands c.lamers@erasmusmc.nl.
Cor H J
CH
Lamers
Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Cancer Institute, 3015 CN Rotterdam, The Netherlands.
Yarne
Y
Klaver
Department of Medical Oncology, Erasmus MC-Cancer Institute, 3015 CN Rotterdam, The Netherlands.
Jan W
JW
Gratama
Department of Medical Oncology, Erasmus MC-Cancer Institute, 3015 CN Rotterdam, The Netherlands.
Stefan
S
Sleijfer
Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Cancer Institute, 3015 CN Rotterdam, The Netherlands.
Reno
R
Debets
D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary*; D016207:Cytokines / Q000097:blood; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D050506:Mutant Chimeric Proteins / Q000627:therapeutic use; D011948:Receptors, Antigen, T-Cell / Q000627:therapeutic use*; D013601:T-Lymphocytes; D016896:Treatment Outcome
D016207:Cytokines; D050506:Mutant Chimeric Proteins; D011948:Receptors, Antigen, T-Cell
adoptive T-cell therapy; carboxy-anhydrase IX; chimeric antigen receptor; clinical study; immune monitoring; on-target toxicity; renal cell cancer