PF-04518600 (PF-8600) and utomilumab (uto) are human IgG2 agonistic mAbs against the tumor necrosis factor superfamily receptors OX40 and 4-1BB, respectively. Both receptors play key roles in T cell survival, proliferation, and activation. PF-8600 has been shown to increase proliferation and activation of peripheral CD4 memory T cells and uto has a similar effect on CD8 memory T cells. Previously, in patients treated with PF-8600, PD changes have been observed in tumor biopsy samples, including enrichment of gene sets associated with immune activation as well as CD4/8 T cell clonal expansion in peripheral blood. PD changes in tumors and peripheral TCR repertoire for PF-8600 + uto are reported here.
Paired biopsy samples at baseline and week 6 were collected from 5 dose cohorts (0.1/20, 0.3/20, 0.3/100, 1.0/100, 3.0/100; dose of PF-8600 in mg/kg / flat dose of uto in mg) during dose escalation. Biopsy tissues were analyzed by IHC and RNAseq to evaluate the PD effects of PF-8600 + uto. CD4, CD8, OX40, and FoxP3 expression was measured by IHC. Changes in transcriptional profile were measured by RNAseq analysis and gene ranking-based gene set enrichment analysis. CD4/8 cells were isolated from blood samples at the same time points. DNA was extracted and submitted for high-throughput sequencing of TCRβ.
In an analysis of paired biopsy samples from dose cohorts including ≥ 0.3 mg/kg PF-8600, OX40 was among the genes that showed increased expression. The top gene sets exhibiting significant enrichment by RNAseq were associated with immune activation. TCR sequencing revealed clonal expansion of CD4/8 T cells at all dose levels.
Increases in immune-related markers including OX40 and enrichment of gene sets associated with immune activation were observed in tumor tissue, providing evidence of an active, immunomodulatory mechanism for PF-8600 + uto. Peripheral CD4/8 T cell populations exhibited clonal expansion at all dose levels, further suggesting an immune-activating PD effect. Further evaluation of PF-8600 + uto safety, efficacy, and PD continues in NSCLC and melanoma cohorts.
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O. Hamid, S. Hu-Lieskovan, J.A. Thompson: Research funding: Pfizer. A.B. El-Khoueiry: Research funding: AstraZeneca and Astex; Consulting honoraria: BMS, Bayer, Eisai, CytomX, EMD Serono. J-P. Spano: Consulting honoraria: Pfizer. N.A. Rizvi: Consulting honoraria: Merck, AstraZeneca, Roche, BMS, Novartis, Pfizer, Lilly, Abbvie, Merck KGaA, Regeneron; Shareholder: Gritstone Oncology, ARMO Biosciences. J.S. Wasser: Research funding: Merck, Incyte, Pfizer, Guardent; Speakers bureau honoraria: Novartis; Consulting honoraria: Amgen; Equity ownership in Pfizer, Merck, Bristol-Meyers Squibb. P.A. Ott: Consulting or advisory role: Amgen, Bristol-Myers Squibb, Alexion, CytomX Therapeutics, Celldex, Genentech, Novartis, Pfizer, Neon Therapeutics; Speaking fees: Merck & Co., Inc.; Research funding to institution: Bristol-Myers Squibb, Merck & Co., Inc., Astra Zeneca/MedImmune, Celldex, Neon Therapeutics, Pfizer, CytomX, and ARMO BioSciences. A. Chiappori: Research funding: AstraZeneca, BMS, Novartis; Consulting/speakers’ bureau honoraria: AstraZeneca, Boehringer, Celgene, Genentech, Merck, Novartis, Takeda. T. Joh, H.I. Krupka, S. Potluri, X. Wang, B.J. Ganguli, J. Chou: Employee: Pfizer at the time of this study. All other authors have declared no conflicts of interest.