Phase 1 study to determine the safety and dosing of autologous PBMCs modified to present HPV16 antigens (SQZ-PBMC-HPV) in HLA-A02+ patients with HPV16+ solid tumors

• Published in: Investigational new drugs 2023-04, Vol.41 (2), p.284-295
• Main Authors: Jimeno, Antonio, Baranda, Joaquina, Iams, Wade T., Park, Jong Chul, Mita, Monica, Gordon, Michael S., Taylor, Matthew, Dhani, Neesha, Leal, Alexis D., Neupane, Prakash, Eng, Cathy, Yeku, Oladapo, Mita, Alain, Moser, Justin C., Butler, Marcus, Loughhead, Scott M., Jennings, Julia, Miselis, Nathan R., Ji, Rui-Ru, Nair, Nitya, Kornacker, Martin, Zwirtes, Ricardo F., Bernstein, Howard, Sharei, Armon
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Anticancer properties; Antigens; Antitumor activity; Biopsy; CD8 antigen; Cell culture; Cell proliferation; Dosage; Exploratory behavior; Feasibility; Histocompatibility antigen HLA; HLA-A Antigens; Human papillomavirus 16; Humans; Immune checkpoint inhibitors; Immune response; Immunotherapy; Leukocytes, Mononuclear; Lymphocytes; Major histocompatibility complex; Medicine; Medicine & Public Health; Metastases; Mice; Microfluidics; Neoplasms - complications; Oncogene Proteins, Viral; Oncology; Papillomavirus E7 Proteins; Papillomavirus Infections - complications; PD-L1 protein; Peripheral blood mononuclear cells; Pharmacodynamics; Pharmacology/Toxicology; Priming; Safety; Solid tumors; Tumors; Veins
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-023-01342-x

Summary We conducted a dose escalation Phase 1 study of autologous PBMCs loaded by microfluidic squeezing (Cell Squeeze ® technology) with HPV16 E6 and E7 antigens (SQZ-PBMC-HPV), in HLA-A*02+ patients with advanced/metastatic HPV16+ cancers. Preclinical studies in murine models had shown such cells resulted in stimulation and proliferation of antigen specific CD8+ cells, and demonstrated antitumor activity. Administration of SQZ-PBMC-HPV was every 3 weeks. Enrollment followed a modified 3+3 design with primary objectives to define safety, tolerability, and the recommended Phase 2 dose. Secondary and exploratory objectives were antitumor activity, manufacturing feasibility, and pharmacodynamic evaluation of immune responses. Eighteen patients were enrolled at doses ranging from 0.5 × 10 6 to 5.0 × 10 6 live cells/kg. Manufacture proved feasible and required < 24 h within the overall vein-to-vein time of 1 – 2 weeks; at the highest dose, a median of 4 doses were administered. No DLTs were observed. Most related TEAEs were Grade 1 – 2, and one Grade 2 cytokine release syndrome SAE was reported. Tumor biopsies in three patients showed 2 to 8-fold increases in CD8+ tissue infiltrating lymphocytes, including a case that exhibited increased MHC-I+ and PD-L1+ cell densities and reduced numbers of HPV+ cells. Clinical benefit was documented for the latter case. SQZ-PBMC-HPV was well tolerated; 5.0 × 10 6 live cells/kg with double priming was chosen as the recommended Phase 2 dose. Multiple participants exhibited pharmacodynamic changes consistent with immune responses supporting the proposed mechanism of action for SQZ-PBMC-HPV, including patients previously refractory to checkpoint inhibitors.