Abstract A044: Initial phase I/IIa trial results of an autologous tumor lysate + yeast cell wall particles + dendritic cells vaccine (TLPLDC) in patients with solid tumors
Authors: Greene Julia M. , Hale Diane F. , Schneble Erika J. , Yu Xianzhong , Nichol Pauline , Yin Sook , Wagner Thomas , Peoples George E. 
Published: May 2016

Abstract
Introduction: The majority of tumor vaccines (vax) target tumor-specific/associated antigens with a variety of delivery systems/immunoadjuvants. As opposed to testing an “off the shelf” vax to treat a subset of patients (pts), our approach is tailored to the specific pt but applicable to all pts, all tumors. Our vax uses autologous dendritic cells (DC) loaded with the full range of tumor antigens from a pt's cancer. Our particle loading system is highly efficient, reducing the need for large tumor volume, high numbers of DC or long culture times. The autologous tumor lysate (TL) is loaded into yeast cell wall particles (YCWP) that are naturally and efficiently taken up into isolated autologous DC. These autologous TL, particle-loaded, DC (TLPLDC) can be produced in 48hrs. Here, we describe the results of the TLPLDC vax in the first 20 pts treated.
Methods: We are conducting an ongoing open label phase I/IIa trial enrolling pts with any solid tumor and treating them with autologous TLPLDC specifically created in our phase I trial center under regulatory oversight. Enrollment criteria include pts with all solid tumors of all stages, with ECOG status ≤1, and &gt;4 months life expectancy. Exclusion criteria are chronic immunosuppression or viral infection and pregnancy. DC are isolated from the pt's peripheral blood monocytes from a 120ml blood draw; cytokines are added to generate immature monocyte-derived DC. A minimum of 1 mg frozen tumor is required from surgery or biopsy. Tumor cells are lysed by multiple freeze/thaw cycles in buffer to produce TL. YCWP are prepared by NaOH digestion of all non-cell wall material from Saccharomyces cerevisiae, followed by washings. These hollow YCWP are loaded with concentrated TL solution via absorption, then freeze dried. Tetanus helper peptide and CpG oligonucleotides are similarly loaded into the YCWP as immunoadjuvants. TLPLDC are generated by incubating TL-loaded YCWP in the presence of DC and cytokines. After phagocytosis, final TLPLDC are frozen in single dose (1x106 cells/dose) vials. After QA/QC testing and lot-release, pts receive 4 monthly intradermal inoculations and then boosters every 6 months for as long as doses last. Trial endpoints are safety and efficacy using CTCAE and RECIST criteria, respectively.
Results: To date, 20 pts have been enrolled to the TLPLDC trial with a median follow-up of 7 mos. The study population is 60% male, 90% Caucasian, 95% stage III/ IV disease (dz), with a median age of 58 years. Tumor types include chondrosarcoma, melanoma, astrocytoma, glioblastoma, Ewing's sarcoma, and renal cell, ovarian, breast, esophageal, pancreatic, squamous cell, bladder, and small cell lung carcinomas. Of the 20 pts, 17 had measurable dz on initiation of treatment, and 3 were vaccinated adjuvantly. Twelve patients completed treatment, 6 are in treatment, and 2 are consented but not initiated. The 12 pts who have completed treatment received a median of 4 inoculations, and no grade ≥3 toxicities have been noted. Flu-like symptoms have been seen in 20%. Of the 17 pts with measurable dz, 10 have completed treatment with 6 demonstrating clinical benefit (1 CR, 2 PR, 3 SD). In the 3 adjuvant pts, 2 have completed treatment, and all 3 remain dz-free at a median follow- up of 10 months.
Conclusions: Current results from this ongoing phase I/ IIa trial indicate that the autologous TLPLDC vax is well-tolerated and safe. The vax appears to have clinical activity in a variety of solid tumors to include melanoma with a complete response. Based on our prior studies with a similar vax and these initial results, TLPLDC may be most efficacious in the minimal residual dz setting; therefore, an adjuvant randomized phase IIb trial in stage III/IV (resected) melanoma pts has been initiated.
Citation Format: Julia M. Greene, Diane F. Hale, Erika J. Schneble, Xianzhong Yu, Pauline Nichol, Sook Yin, Thomas Wagner, George E. Peoples. Initial phase I/IIa trial results of an autologous tumor lysate + yeast cell wall particles + dendritic cells vaccine (TLPLDC) in patients with solid tumors. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A044.