Phase 1b/2 prospective randomized trial of four autologous cell vaccine dose cohorts for initial treatment of glioblastoma.

Introduction: We present a novel autologous cell vaccine therapy designed to treat patients with newly diagnosed glioblastoma (Trial Registration: IND 14379, NCT01550523). Methods: This phase 1b trial has a phase 2 design with 4 randomized vaccine dose cohorts in 33 patients with the objective being safety assessment but also including clinical, radiographic, and immune analyses. Eligibility criteria included age \u003e 18 and Karnofsky score of \u003e 60; neither bihemispheric disease nor extent of resection were exclusion criteria but autoimmune diseases were. During craniotomy for tumor resection, if frozen section confirmed GBM, incisions were made in the lower abdomen through the rectus sheath and pockets created between the sheath and the muscle and the wounds closed with a temporary three-layer closure. Tumor resection involved an aspirator that collected morselized viable tumor tissue in sterile traps. The tissue was processed by overnight culture with 0.2 mg of an IGF-1R antisense oligodeoxynucleotide/gm. The next (first postoperative) day, treated tumor cells were harvested, encapsulated in either ten or twenty small biodiffusion chambers along with 4 micrograms of the IGF-1R antisense, irradiated and then implanted at bedside in the abdominal acceptor sites as previously described (1). Chambers were explanted 24 or 48 hours later, depending on randomization. Standard of care according to Stupp (2) was initiated at 6 weeks. Studies included 3T MRI imaging and analysis of serial blood samples for T cell function and cytokine levels. Disease progression was assessed using RANO (3) and iRANO (4) criteria with a data cutoff of March 1 (N=30) used for this analysis. Results: The trial opened September 1, 2015 and completed accrual on March 1, 2018. A midpoint interim analysis revealed significantly more robust cytokine responses at the highest vaccine dose. Randomization was therefore stopped at subject 23 and amended to treat using only the highest dose. Progression-free survival (PFS) was compared to three historic SOC comparators (Stupp [2], Kong [5], and an antecedent cohort of 37 consecutive patients treated with SOC at our institution [TJUH]). PFS was significantly improved at 10.5 mo v. SOC comparators: 6.9 mo (Stupp, p = .003), 5.3 mo (Kong, p = .002) and 7 mo (TJUH, p = .013). Seventy-five percent of the 14 patients in the highest-dose cohort had robust proinflammatory and early evidence of sustained immune reactivity associated with tumor regression or no recurrence after surgery. Conclusion: These data reflect a therapeutic benefit defined as significant improvement in PFS without increased safety risk compared to three different SOC cohorts. Since GBM remains one of the most challenging solid tumors, this treatment design invites investigator collaboration in a multicenter phase 2 trial. References: 1. Andrew et al. J Clin Oncol 19:2189-2200; 2. Stupp et al. NEJM 352:987-96; 3. Wen et al. J Clin. Oncol 28:1963-72; 4. Okada et al. Lancet Oncol 16:534-42; 5. Kong et al. Oncotarget 8:7003-13. Citation Format: Kevin D. Judy, David W. Andrews, Larry Harshyne, Lawrence Kenyon, Kiran Talekar, Kofi-Buaku Atsina, Lyndon Kim, Wenyin Shi, Maria Werner-Wasik, Rhonda Kean, Samantha Garcia, Kara Pigott, Charles B. Scott, D. Craig Hooper. Phase 1b/2 prospective randomized trial of four autologous cell vaccine dose cohorts for initial treatment of glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B71.