Therapeutic Potential of Increased Intratumoral Cytotoxic CD8+T Cells Following Antibody-Induced CTLA4 Blockade in Metastatic Melanoma
RR Huang, AJ Cochran, A Ribas. UCLA David Geffen School of Medicine, Los Angeles, CA
Background: Blockade of CTLA4 (a major inhibitor of anti-cancer cellular immunity) induces persistent responses in ∼10% of patients with metastatic melanoma. Though not prospectively demonstrated in humans, preclinical models predict that CTLA4 blockade will increase T cell accumulation in tumors. We quantified immune infiltrates in biopsies of patients treated with the fully human anti-CTLA4 monoclonal-antibody tremelimumab (Pfizer Inc).
Design: Pre- and post-treatment biopsies (pre-bx and post-bx) from 20 patients with advanced melanoma (SIIIc-M1) treated with tremelimumab (15 mg/kg q3 months) were evaluated for density of intratumoral infiltrates (ITI) and peritumoral infiltrates (PTI) by CD4+ThLs and CD8+CTLs using IHC and computer-based imaging system analyses.
Results: CD8+CTL ITI was 955.06±621.08/mm2 in post-bx vs. 296.12±278.85 in pre-bx (mean increase: 658.94, P=0.0006). CD4+ThLs ITI post-bx was 305.52±116.20/mm2 vs. 116.20± 141.52 pre-bx (mean increase 189.31, P=0.0004). CD8+CTLs PTI was 1099.81±1034.45/mm2 in post-bx vs. 568.57±513.86 in pre-bx (mean increase: 531.23; P=0.1309). CD4+ThL PTI was 777.74±694.96/mm2 post-bx vs. 439.64±377.46 pre-bx (mean increase: 338.09; P=0.2661). CD8 infiltration and associated regression of melanoma paralleled clinical responses. 3 patients had a durable complete clinical response after treatment of tremelimumab: 1 with rare individual melanoma cells left swamped by CD8+CTL (post vs. pre: 958.19 vs. 140.48) with concomitant increase in CD4+ThL (1142.27 vs.142.19) infiltration; 1 with very dense T cell infiltration (ITI-post vs. pre: CD8+CTLs 955.79 vs. 77.95; CD4+ThL 545.65 vs. 0.00); another patient had a delayed biopsy that showed fibrotic replacement of a regressed melanoma. Patients without clinical responses also had marked increases of ITI density in post-bx after treatment: in 8 patients the increase of CD8+CTLs density was greater than the average increase (658.94); 6 patients had an increase of CD4+ThLs density greater than average (189.31).
Conclusions: The CTLA4 blocking antibody tremelimumab significantly increases intratumoral infiltration by CD8+ CTL and CD4+ThL, demonstrating markedly enhanced immune infiltration of tumors in most patients. This provides direct evidence of one component of the mechanism by which this antibody induces durable tumor responses in metastatic melanoma patients. Since some patients have increased CTL, but do not respond clinically, there are clearly other factors involved that remain to be explored.
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 79, Wednesday Afternoon