By analyzing tumor biopsies from 51 patients in the phase 2 trial for Axicabtagene ciloleucel (anti-CD19 CAR T cell therapy approved for r/rLBCL), Scholler et al. showed differences between the rapid (2-4 wk) broad changes in immune profiles in the post-treatment TME of responders and nonresponders. Patients with high Th cell TME density and low tumor burden had CR and higher T cell TME density pre- and post- therapy. Low blood CAR T cell expansion was associated with exhausted CTLs in the post-treatment TME. High Treg cell density in the pre-treatment TME was associated with less therapy-related neurologic toxicity and, unexpectedly, other favorable TME features.
Contributed by Paula Hochman
ABSTRACT: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell subsets were validated in three independent LBCL datasets. In the ZUMA-1 trial samples, clinical response and overall survival were associated with pre-treatment immune contexture as characterized by Immunoscore and Immunosign 21. Circulating CAR T cell levels were associated with post-treatment TME T cell exhaustion. TME enriched for chemokines (CCL5 and CCL22), γ-chain receptor cytokines (IL-15, IL-7 and IL-21) and interferon-regulated molecules were associated with T cell infiltration and markers of activity. Finally, high density of regulatory T cells in pre-treatment TME associated with reduced axi-cel-related neurologic toxicity. These findings advance the understanding of LBCL TME characteristics associated with clinical responses to anti-CD19 CAR T cell therapy and could foster biomarker development and treatment optimization for patients with LBCL.
Author Info: (1) Kite, a Gilead company, Santa Monica, CA, USA. Gilead Sciences, Foster City, CA, USA. (2) Veracyte SAS, Marseille, France. (3) Moffitt Cancer Center, Tampa, FL, USA. (4) Moffit
Author Info: (1) Kite, a Gilead company, Santa Monica, CA, USA. Gilead Sciences, Foster City, CA, USA. (2) Veracyte SAS, Marseille, France. (3) Moffitt Cancer Center, Tampa, FL, USA. (4) Moffitt Cancer Center, Tampa, FL, USA. (5) Veracyte SAS, Marseille, France. (6) Veracyte SAS, Marseille, France. (7) Kite, a Gilead company, Santa Monica, CA, USA. (8) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Stanford University School of Medicine, Stanford, CA, USA. (10) Dana-Farber Cancer Institute, Boston, MA, USA. (11) University of Miami Health System, Sylvester Comprehensive Cancer Center, Miami, FL, USA. (12) Mayo Clinic, Rochester, MN, USA. (13) Washington University School of Medicine, St. Louis, MO, USA. (14) Kite, a Gilead company, Santa Monica, CA, USA. (15) Kite, a Gilead company, Santa Monica, CA, USA. (16) Kite, a Gilead company, Santa Monica, CA, USA. (17) Kite, a Gilead company, Santa Monica, CA, USA. (18) Kite, a Gilead company, Santa Monica, CA, USA. (19) Kite, a Gilead company, Santa Monica, CA, USA. (20) Kite, a Gilead company, Santa Monica, CA, USA. (21) Kite, a Gilead company, Santa Monica, CA, USA. Capstan Therapeutics, San Diego, CA, USA. (22) Veracyte SAS, Marseille, France. jerome.galon@crc.jussieu.fr. INSERM, Sorbonne Université, Université Paris Cité, Centre de Recherche des Cordeliers, Equipe Labellisée Ligue Contre le Cancer, Laboratory of Integrative Cancer Immunology, Paris, France. jerome.galon@crc.jussieu.fr.
