Ramirez-Segura, Cesar A

Background: Chimeric Antigen Receptor (CAR) T cell therapy is a promising cancer immunotherapy that is growing exponentially. The doubling time of medical knowledge in 2010 was 3.5 years, and the projection for 2020 is just 73 days. In the last five years, the number of PubMed publications on cancer applications of CAR T cells has tripled. Therefore, to remain updated in the field represents a challenge for patients, care providers and researchers. In this review we provide a focused summary of the currently ongoing clinical trials, with a comprehensive overview of advances in CAR T cell therapy, beyond CD19, emphasizing on antigenic targets, development phases, and leading sponsor pharmaceutical companies. Methods: We retrieved the available data from the national registry of clinical trials (clinicaltrials.gov) using the following keywords: "CAR T cell", "CAR T cell and cancer", "chimeric antigen receptor", "CAR T AND tumor antigen", 'CAR T cell antigens", "Tumor antigens targeted by CAR T cells", "engineered T cells", "modified T cell", "CAR T cells in Cancer", "CAR T cell therapy", "CAR T cell therapy AND Cancer" until December 31, 2018 and manually excluded the trials unrelated to CAR T-cell therapies on cancer, by reviewing the detailed information provided on the website as well as preliminary data published. Results: The analysis included 271 clinical trials posted on the clinicaltrials.gov website from the United States by the cut-off date. For efficacy analysis, we retrieved information from 52 trials, by NCT number on a PubMed search. The majority of CAR T clinical research is focused on hematological cancer (57%), followed by CNS 8%, GI 6%, Skin 5%, Genitourinary 4%, Breast 4%, Gynecologic 4%, Respiratory 3%, Sarcoma 2%, Mesothelioma 2% and others 5%. The most used target in CAR T cell therapy and the leaders in phase 3 trials are CD19 (42%) and BCMA (12%), followed by CD20, NY-ESO-1, Mesothelin, HER2, GD2, MAGE-A3 and CD30. An essential step in CAR T cell therapy development is the selection of the right antigen/target. Here, we provide an overview of the clinically relevant targets that are actively being using by clinical trials in the United States. For example, CD19 appears to be a leading target regarding CAR T cell therapy on cancer with 116 trials (42% of total CAR T cells trials) on going just in the United States with a significant increment in the previous years. Similarly, with BCMA is one of the targets with more phase 3 trials (Figure 1) with promising results on patients with Multiple Myeloma with and the objective response of 85%, CR 45%, and PFS of 11.8 months. Second-generation CARs with either CD28 or 4-1BB as costimulatory signaling domain are preferred, with 4-1BB being the most commonly chosen. Conclusions: Our findings show growing trends in the development of CAR T cell-based therapies, combination and possible retargeting therapies in the future for solid tumor and hematologic malignances; taking into account the amount of important information and the complexity of the database, we have developed this analysis to understand how to generate in the future a friendly platform for researchers and patients to have an detailed overview of the clinical trials in cellular therapies Disclosures No relevant conflicts of interest to declare.

Abstract Obinutuzumab-Gazyva (G) is an anti-CD20 monoclonal antibody that has shown better outcomes in patients (pts) with chronic lymphocytic leukemia and low-grade lymphoma (Goede 2014, Marcus 2017). However, one limitation for its use when compared to Rituximab is the presence of significantly more frequent and more severe infusion related reactions (IRR). Strategies to mitigate this significant adverse event are needed particularly to allow a safer administration of this antibody to elderly pts or those with existing comorbidities. We have observed a reduction of G-induced IRR in previously untreated CLL pts that are enrolled on a phase Ib/II clinical trial (NCT02315768) that combines G with the Bruton's tyrosine kinase inhibitor, ibrutinib (Ibr). Only 5 out of 23 pts treated have developed IRR (Grade 1-2, 17% and Grade 3, 4%). This rate of IRR is much lower as compared with rates previously reported (all grades: 65%, grade 3-4: 20% - Goede 2014), (all grades: 92%, grade 3-4: 26.3% - Freeman,2015). Moreover, there were no pts that require permanent discontinuation of G due to IRR. To understand the biology of this beneficial effect of Ibr, we performed serial cytokine measurements on plasma samples from 23 pts enrolled in this study at different time points during the first week of combined treatment (Cycle 1 prior to the first infusion of G and post G infusion on Day 1, Day 2 and Day 8) - Figure 1. We developed a multiplex assay (Luminex) to measure 7 different cytokines previously reported to be involved in IRR (IFN-g, IL-10, IL6, IL8, CCL3/MIP1-a, CCL4/MIP1-band TNF-a). Standards were set up in duplicate yielding curves from 3.2 pg/ml to 10.000 pg/ml. Assays were performed according to manufacturer's instructions, with undiluted samples and overnight agitated incubation at 4 °C. We identified the maximum peak of cytokine levels post G infusion and compared those values with the baseline cytokine profile obtained prior to the first G infusion on Cycle 1 Day 1. The majority of pts (22 out of 23) showed cytokines maximum peaks in the middle of G-infusion during Cycle 1 Day 1 and this correlated with the onset of IRR associated symptoms in those pts that reacted to G. With the exception of IL-6, we observed statistically higher post vs. pre G infusion levels of TNF-a(p=0.0012), IFN-g(p=<0.0001), CCL3 (p=0.0458), CCL4 (p=<0.0001), IL-8 (p=<0.0001), and IL-10 (p=<0.0001) even in pts that did not develop IRR. However, the post infusion peak levels of TNF-a(p=0.0043), IFN-g(p=0.0457) and CCL3 (p=0.0460) were significantly higher in pts with IRR compared to those that had no IRR. Baseline levels prior to G infusion of TNF-a(p=0.0495) and IFN-g(p=0.0301) were higher in IRR pts, suggesting a possible predictive role in the development of IRR. Figure 1. Our study shows that concurrent administration of Ibr (Initiated on Cycle 1 Day 1 with pre-medications) and G shows a beneficial effect decreasing the rates of IRR (Amaya-Chanaga, 2016). All pts showed a significant increase of cytokine levels post G infusion with IL-6 levels being the exception. When we compared post G infusion cytokine levels, we observed that IRR-pts had a significant increase in TNF-a, IFN-g, and CCL3 suggesting a role of these cytokines in the clinical manifestations associated with IRR. In addition, higher levels of TNF-a and IFN-g, at baseline prior to G infusion appear to be predictive of the development of IRR. Even though our sample size is small, our observations provide additional insights into the biology of G associated IRR and how to decrease effectively those adverse events using Ibr while preserving the immune function needed for the activity of this monoclonal antibody. In addition, Ibr induced modulation of signaling through the B cell receptor and patterns of cytokine release might be efficacious in preventing other monoclonal antibody IRR as well as those reactions observed in pts that receive adoptive cellular therapy (i.e. CART cell treatment). Disclosures Choi: AbbVie, Inc: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Genentech: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Kipps:Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech Inc: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Castro:F. Hoffmann-La Roche: Consultancy; Genentech, Inc: Consultancy; Pharmacyclics, LLC, an AbbVie Company:: Consultancy.