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Download PDF Document Journal for ImmunoTherapy of Cancer 2019, 7(Suppl 1):283 https://doi.org/10.1186/s40425-019-0764-0 MEETINGABSTRACTS Open Access 34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019): part 2 National Harbor, MD, USA. 10 November 2019 Published: 6 November 2019 About this supplement These abstracts have been published as part of Journal for ImmunoTherapy of Cancer Volume 7 Supplement 1, 2019. The full contents of the supplement are available online at https://jitc.biomedcentral.com/articles/supplements/volume-7-supplement-1. Please note that this is part 2 of 2. Poster Presentations median survival; 3) FTN203 did not negate the efficacy of anti- PD-1 or anti-PD-L1 immunotherapy antibody when combined; 4) Biomarkers, Immune Monitoring, and Novel FTN203 significantly improved the efficacy of anti-PD-1 by further Technologies reducing the tumor growth (by 80% on day 26, P=0.046) and in- creasing the median survival (by 5 days or 14%, Log-rank test P= P501 0.031), against the combo of COMPLETE and anti-PD-1; 5) None Dietary deprivation of non-essential amino acids improves anti-PD- of the mono or combo treatments caused body weight loss. 1 immunotherapy in murine colon cancer Conclusions Zehui Li, PhD, Grace Yang, PhD, Shuang Zhou, PhD, Xin Wang, MD, PhD, Our data supports the use of dietary NEAA deprivation to improve Xiyan Li, PhD the efficacy of anti-PD-1 or anti-PD-L1 immunotherapy for colorectal Filtricine, Inc., Santa Clara, CA, United States cancer without noticeable side effects. With further development, Correspondence: Xin Wang ([email protected]), Xiyan Li dietary NEAA deprivation may become the promising foundation for ([email protected]) a broad spectrum of cancer therapies. Journal for ImmunoTherapy of Cancer 2019, 7(Suppl 1):P501 Ethics Approval The study CA-XLI-6 was approved by the CRO's Ethics Board under Background IACUC approval number 19-015.9. Cancer cells require outside supply of some non-essential amino acids (NEAAs) to survive. Dietary deprivation of select (NEAAs) can slow down the growth of multiple solid tumors in mice, creating a new non-drug strat- P502 egy in cancer treatment. However, deprivation of NEAAs could negatively In vitro and in vivo RRx-001 synergy with regorafenib and in vivo impact the immune activation, an essential process for immunotherapy, be- attenuation of regorafenib-induced toxicity cause fast cell proliferation poses a higher demand for building blocks such Bryan Oronsky, MD PhD1, Tony Reid, MD PhD2, Corey Carter, MD2, 2, as NEAAs. It is not clear whether dietary NEAA deprivation could be com- Pedro Cabrales, PhD3 bined with immunotherapy for better safety-efficacy profiles. 1EpicentRx Inc, La Jolla, CA, United States; 2EpicentRx, Inc., La Jolla, CA, Methods United States ; 3University of California San Diego (UCSD), La Jolla, CA, In this study, we tested the effects of NEAA-deprived diets and checkpoint United States inhibitor anti-PD-1 and anti-PD-L1 in colon cancer using syngeneic mouse Correspondence: Christopher Larson ([email protected]) model (Balb/c) bearing tumors of mouse colorectal cancer cell line CT-26. Journal for ImmunoTherapy of Cancer 2019, 7(Suppl 1):P502 Three diets were tested, including a natural rodent diet Teklad ENVIGO Glo- bal 16% Protein Rodent Diet (control 1), a formulated NEAA-complete diet Background COMPLETE (control 2, using amino acid mix in place of protein), and a for- In the Phase 3 CORRECT study, which led to the approval of the mulated NEAA-deprived diet FTN203 (treatment, using amino acid mix in multi-kinase inhibitor, Regorafenib, in 3rd/4th line metastatic colo- place of protein). Both COMPLETE and FTN203 have the same nutritional rectal cancer, the OS was 6.4 months and the PFS was 1.9 structures, contain 17% w/w protein equivalent, and are isocaloric. After months compared to an OS of 5.0 months and a PFS of 1.7 tumor size-based randomization, these diets were provided to mice ad libi- months for placebo. However, Regorafenib is very poorly toler- tum throughout the whole test. Each of these diets was used alone or com- ated with a Grade 3/4 drug related adverse event rate of 54%, bined with anti-PD-1 antibody (i.p., twice per week for 2 weeks) or anti-PD- mostly due to hand-foot skin reactions, fatigue and diarrhea, L1 antibody (i.v., twice per week for 2 weeks). resulting in frequent dose reductions and discontinuations and a Results general reluctance among GI oncologists to administer it. RRx-001 We found 1) On day 24 post tumor implantation, NEAA-deprived is a minimally toxic macrophage repolarizing agent in Phase 3 diet FTN203 significantly reduced tumor growth when used clinical trials that is associated with a reduced side effect profile alone, compared to the group fed with Teklad ENVIGO (by 81%, from these chemotherapy agents. Recent studies have demon- P=0.0054, unpaired t-test after Welch correction) and COMPLETE strated the inhibitory impact of M2 macrophages on the activity (by 81%, P=0.013), respectively; 2) The efficacy of FTN203 is com- of tyrosine kinases suggesting that the repolarization of macro- parable with that of anti-PD-1 or anti-PD-L1 in tumor growth and phages by RRx-001 may enhance the activity of TKIs. © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Journal for ImmunoTherapy of Cancer 2019, 7(Suppl 1):283 Page 2 of 237 Methods other treatment groups. Further information, including full tumor These experiments determined whether combination therapy with growth and immunological mechanism-of-action data will be RRx-001 and regorafenib not only enhanced anticancer activity presented. in vitro with HCT-116 and HCT-15 colorectal cell lines and in vivo Conclusions with HCT 116 and HCT 15 xenografts but also attenuated the toxicity These two cancer immunotherapies seem to be a promising ap- of regorafenib in these two xenografts. proach that could increase survival upon clinical translation. It is of Results importance that systemic anti-tumor effects result from local injec- The results from these experiments demonstrate that 1) RRx-001 + regoraf- tion of adenovirus coding TNF- α and IL-2, even in the absence of enib is more effective than either agent alone both in vitro and in vivo and virus replication. that 2) the addition of RRx-001 to regorafenib attenuates the toxicity of re- gorafenib in vivo. Acknowledgements Conclusions We thank the Biomedicum FACS Core facility and the Animal the Finnish A clinical trial is planned to investigate the translational potential Centre for Laboratory Animal Pathology (FCLAP) at the University of Helsinki, of the RRx-001 + regorafenib combination. Future experiments for their expert assistance. This is study was supported by Jane and Aatos will determine whether RRx-001 also enhances the activity and Erkko Foundation, HUCH Research Funds (EVO), Sigrid Juselius Foundation, decreases the toxicity of other tyrosine kinase inhibitors such as Finnish Cancer Organizations, University of Helsinki, The Finnish Society of sorafenib, sunitinib, dasatinib, imatinib, lapatinib, and cabozanti- Sciences and Letters, and TILT Biotherapeutics Ltd. nib, all of which possess similar efficacy and safety profiles, not Ethics Approval only in colorectal cancer but also other tumor types. All experiments described here have been approved by The Gene Technology Board of Finland, by the Experimental Animal Committee of the University of Helsinki and the Provincial Government of Southern Finland, P503 under the license number ESAVI/7755/04.10.07/2016. Local treatment with adenovirus expressing TNF-α and IL-2 proteins promotes abscopal effect in mice receiving anti-PD-1 References immunotherapy 1. Mole RH. Whole Body Irradiation—Radiobiology or Medicine? Br J Radiol. Dafne Quixabeira, MSc, Victor Cervera-Carrascon, MS, Joao Santos, MS, 1953; 305: 234-241. Riikka Havunen, Akseli Hemminki, MD, PhD 2. Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, University of Helsinki, Helsinki, Finland Formenti SC. Immune-Mediated Inhibition of Metastases after Treatment Correspondence: Akseli Hemminki ([email protected]) with Local Radiation and CTLA-4 Blockade in a Mouse Model of Breast Journal for ImmunoTherapy of Cancer 2019, 7(Suppl 1):P503 Cancer. Clin Cancer Res. 2005; 15:728-34. 3. Havunen R, Santos JM, Sorsa S, Rantapero T, Lumen D, Siurala M, Airaksinen Background AJ, Cervera- Carrascon V, Tähtinen S, Kanerva A, and Hemminki A. Abscopal Treatment of metastatic solid tumors remains a challenge in on- Effect in Non-injected Tumors Achieved with Cytokine-Armed Oncolytic cology, especially in the context of locally given therapies. Some Adenovirus. Mol Ther Oncolytics. 2018; 11: 109–121. responses in non-treated metastases were described in the mid- 4. Cervera-Carrascon V, Siurala M, Santos JM, Havunen R, Tähtinen S, dle of the last century after using local radiotherapy in breast Karell P, Sorsa S, Kanerva A, Hemminki A.TNFa and IL-2 armed adeno- cancer patients. This phenomenon was named abscopal effect[1]. viruses enable complete responses by anti-PD-1 checkpoint blockade. Nowadays, this effect is known to be elicited by systemic adap- Oncoimmunology. 2018; 9;7(5):e1412902. doi: 10.1080/ tive immune responses against tumor cells, following local treat- 2162402X.2017.1412902.
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