Despite efforts to develop increasingly targeted and personalized cancer therapeutics, dosing of drugs in cancer chemotherapy is limited by systemic toxic side effects. We have designed, built, and deployed porous absorbers for capturing chemotherapy drugs from the bloodstream after these drugs have had their effect on a tumor, but before they are released into the body where they can cause hazardous side effects. The support structure of the absorbers was built using 3D printing technology. This structure was coated with a nanostructured block copolymer with outer blocks that anchor the polymer chains to the 3D printed support structure and a middle block that has an affinity for the drug. The middle block is polystyrenesulfonate which binds to doxorubicin, a widely used and effective chemotherapy drug with significant toxic side effects. The absorbers are designed for deployment during chemotherapy using minimally invasive image-guided endovascular surgical procedures. We show that the introduction of the absorbers into the blood of swine models enables the capture of 64 ± 6% of the administered drug (doxorubicin) without any immediate adverse effects. Problems related to blood clots, vein wall dissection, and other biocompatibility issues were not observed. This development represents a significant step forward in minimizing toxic side effects of chemotherapy.

T cells capable of targeting neoepitopes (neoE) from tumor-specific mutations hold the potential to uniquely recognize and kill tumor cells. However, most cancer patients fail to mount a sufficient intrinsic T cell immune response to translate into clinical benefit. PACT Pharma has developed an ultra-sensitive and high-throughput technology (imPACT) for identifying and isolating neoE-specific T cells from peripheral blood. Whole exome sequencing of tumors and computational prediction identify patient-specific neoepitopes resulting from tumor-specific mutations. We then interrogate patient blood for neoE-specific T cells using human leukocyte antigen (HLA) protein-based reagents comprising a spectrum of human HLAs, thus enabling the evaluation of >99% of all individuals with cancer. We have identified and isolated neoE-specific T cells from the peripheral blood of >80% treatment-naive patients with bladder and colorectal cancers, melanoma and other solid tumors. Primary human T cells engineered with T cell receptor sequences (TCRs) cloned from the imPACT-isolated T cells gain the ability to kill cognate neoE-presenting tumor cells, thereby also confirming the specificity of the isolated TCR sequences to bind to the neoE target. This approach is also amenable to the longitudinal analysis of patients undergoing treatment for their cancers, to characterize the neoE-specific T cell populations likely to confer clinical benefit. In summary, the imPACT technology efficiently discovers potentially meaningful intrinsic neoE-specific TCRs from patients, enabling the development of personalized neoTCR-T cell therapies for the eradication of solid tumors. Citation Format: Songming Peng, Boi Quach, Duo An, Salemiz Sandoval, Robert Bao, Zheng Pan, Michael Bethune, Olivier Dalmas, Michael Yi, Corey Meadows, Katherine Heeringa, Linlin Guo, Benjamin yuen, John Sorfleet, Kyle Jacoby, Robert Moot, William Lu, Diana Nguyen, Barbara Sennino, Andrew Conroy, Bhamini Purandare, Adam Litterman, Stefanie Mandl, Alex Franzusoff. An ultra-sensitive and high-throughput technology (imPACT) for the identification and isolation of intrinsic and emergent neoepitope-specific T cells from the peripheral blood and TILs of cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1435.

T cells targeting neoepitopes derived from mutations exclusive to the tumor are one of the main drivers of cancer immunotherapy efficacy. Tracking these neoepitope-specific T cells during cancer immunotherapy has been hampered by the impracticality of repeated sampling from the tumor, and by the low frequency of neoepitope-specific T cells in peripheral blood. An ultra-sensitive and high-throughput technology (imPACT) has been developed for the identification and isolation of neoepitope-specific T cells from peripheral blood. Subjects with colorectal cancer, endometrial adenocarcinoma, nasopharyngeal carcinoma and other solid tumors were treated with AB122 (anti-PD-1 antibody) as part of an ongoing dose-escalation clinical trial. Pre-treatment blood samples were analyzed to identify the basal repertoire of neoepitope-specific T cells. Evolution of this repertoire during AB122 treatment was monitored to enable immune phenotyping and correlation with clinical outcomes. In addition, transcriptional profile changes were monitored at the single-cell level for each neoepitope-specific T cell. These data will enable us to analyze T cells targeting neoepitopes and identify driver mutations that correlate with and may be responsible for therapeutic benefit. More broadly, this platform technology promises to significantly advance our understanding of T cell-mediated mechanisms of cancer immunotherapy. Citation Format: Songming Peng, Benjamin Yuen, Joanne Tan, Fangfang Yin, Robert Bao, Zheng Pan, Olivier Dalmas, Duo An, Boi Quach, Michael Yi, Michael Bethune, Stefanie Mandl, Matt Walters, Juan Jaen, Alex Franzusoff. Longitudinal monitoring of neoepitope-specific T cell repertoires in patient blood following cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4042.