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Developmental Therapeutics Immunotherapy DEVELOPMENTAL THERAPEUTICS—IMMUNOTHERAPY 2500 Oral Abstract Session Clinical activity of systemic VSV-IFNb-NIS oncolytic virotherapy in patients with relapsed refractory T-cell lymphoma. Joselle Cook, Kah Whye Peng, Susan Michelle Geyer, Brenda F. Ginos, Amylou C. Dueck, Nandakumar Packiriswamy, Lianwen Zhang, Beth Brunton, Baskar Balakrishnan, Thomas E. Witzig, Stephen M Broski, Mrinal Patnaik, Francis Buadi, Angela Dispenzieri, Morie A. Gertz, Leif P. Bergsagel, S. Vincent Rajkumar, Shaji Kumar, Stephen J. Russell, Martha Lacy; Mayo Clinic, Rochester, MN; The Ohio State University, Columbus, OH; Mayo Clinic, Scottsdale, AZ; Division of Hematology, Mayo Clinic, Roches- ter, MN; Vyriad and Mayo Clinic, Rochester, MN Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach for relapsed re- fractory hematologic malignancies. The Indiana strain of Vesicular Stomatitis Virus was engineered to encode interferon beta (IFNb) and sodium iodine symporter (NIS) to produce VSV-IFNb-NIS. Virally en- coded IFNb serves as an index of viral proliferation and enhances host anti-tumor immunity. NIS was in- serted to noninvasively assess viral biodistribution using SPECT/PET imaging. We present the results of the phase 1 clinical trial NCT03017820 of systemic administration of VSV-IFNb-NIS among patients (pts) with relapsed refractory Multiple Myeloma (MM), T cell Lymphoma (TCL) and Acute myeloid Leu- 9 kemia (AML). Methods: VSV-IFNb-NIS was administered at 5x10 TCID50 (50% tissue culture infec- 11 tious dose) dose level 1 to dose level 4, 1.7x10 TCID50. The primary objective was to determine the maximum tolerated dose of VSV-IFNb-NIS as a single agent. Secondary objectives were determination of safety profile and preliminary efficacy of VSV-IFNb-NIS. Correlative objectives included monitoring viremia and virus shedding. Adverse events (AEs) are reported based on CTCAE V4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014) criteria. Results: 15 pts received VSV-IFNb- NIS: MM (7), TCL(7) and AML(1); 3 pts were treated at each dose level (DL) 1 through 3 (respectively 11 11 0.05, 0.17, and 0.5 x 10 TCID50), & 6 pts were treated at dose level 4 (1.7x10 TCID50). There were no dose limiting toxicities. The most frequent grades 3 & 4 AEs were hematologic: lymphopenia (46.6 & 26.6%), neutropenia (13.3% & 6.7%). CRS grades 1 (6.7%) and 2 (46.6%) were the non-he- matologic AEs of note; mostly at DL 4. Only 1 pt required transient pressor support. Responses were seen in pts with T cell lymphoma. At DL2, there was a partial response (PR) lasting 3 months in a pt, post 12 prior lines of therapy. At DL4 there was a 6 month PR in a pt with PTCL and another pt with cu- taneous relapse of PTCL who enjoys an ongoing CR, more than 1 year post VSV infusion; both pts re- ceived 5 prior lines of therapy. Viremia was detected in all pts at the end of infusion only up to 72 hrs post infusion; no infectious virus was recovered in buccal swabs or urine. Neutralizing anti-VSV antibod- ies were present by day 29. IFN levels were detectable within 30 mins of infusion, peaking between 4 & 48 hrs. TCL pts mounted higher hIFNb levels within 48 hrs; the pt with CR mounted peak hIFNb re- sponse of 18213.3pg/ml at 48 hrs post infusion, 15-fold higher than any other pt. Conclusions: VSV- IFNb-NIS can be safely administered by IV infusion among heavily pretreated pts with hematologic ma- lignancies. VSV-IFNb-NIS as a single agent appears to be most effective at DL4 among patients with TCL, with an ongoing CR in a patient at DL4 more than 1 year post administration. Future trials of com- bination strategies with immune-modulatory drugs are currently being planned. Clinical trial information: NCT03017820. Research Sponsor: Mayo Myeloma SPORE. © 2021 by American Society of Clinical Oncology. Visit abstracts.asco.org and search by abstract for disclosure information. DEVELOPMENTAL THERAPEUTICS—IMMUNOTHERAPY 2501 Oral Abstract Session Phase II evaluation of the triple combination of PDS0101, M9241, and bintrafusp alfa in patients with HPV 16 positive malignancies. Julius Strauss, Charalampos S. Floudas, Houssein Abdul Sater, Michell Manu, Elizabeth Lamping, Deneise C Francis, Lisa M. Cordes, Jenn Marte, Renee Nicole Donahue, Caroline Jochems, Jason Redman, Ravi Amrit Madan, Marijo Bilusic, Fatima Karzai, Scott Norberg, Christian S. Hinrichs, Lauren V Wood, Frank K Bedu-Addo, Jeffrey Schlom, James L. Gulley; Laboratory of Tumor Immunology and Biology, NCI, NIH, Bethesda, MD; Genitourinary Malignancies Branch, NCI, NIH, Bethesda, MD; NIH, Bethesda, MD; Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD; National Cancer Institute-National Institute of Health, Be- thesda, MD; National Cancer Institute at the National Institutes of Health, Bethesda, MD; PDS Biotech- nology, Princeton, NJ; Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD Background: There are more than 630,000 cases of HPV associated malignancies including cervical, oropharyngeal and anal cancer worldwide annually. HPV 16 is responsible for the majority of these cases. About 15-20% of HPV associated malignancies respond to PD-(L)1 inhibitors, but for the over- whelming majority of patients who progress on these immunotherapies there is no effective standard of care therapy. Preclinical studies have shown that the triple combination of PDS0101 (Versamune- HPV), a liposomal multipeptide therapeutic vaccine targeting HPV 16 E6/E7, M9241, a tumor-target- ing immunocytokine composed of IL-12 heterodimers fused to a monoclonal antibody targeting free DNA in necrotic tumor regions, and bintrafusp alfa, a bifunctional fusion protein targeting TGF-b and PD-L1, resulted in maximum HPV-specific T cell responses, T cell tumor infiltration and tumor reduc- tion as compared to any one or two of these agents alone. Methods: Fourteen pts with HPV 16+ relapsed or refractory advanced cancer were enrolled to the triple combination of PDS0101, M9241 and bintra- fusp alfa (NCT04287868). Pts received bintrafusp alfa at 1200 mg flat dose i.v. every 2 weeks, M9241 at 16.8 mcg/kg s.c. every 4 weeks and PDS0101 given as two separate 0.5 ml s.c. injections every 4 weeks. Dose reductions of M9241 to 8 mcg/kg were allowed as well as skipped doses of any agent for ongoing toxicities. Results: Fourteen pts with advanced HPV 16+ cancers (5 cervical, 2 vagi- nal/vulvar, 4 anal, 3 oropharyngeal) were treated. 4/14 (28.6%) pts had a grade 3 treatment related tox- icity including grade 3 hematuria in 2 pts with cervical ca and prior pelvic radiation and grade 3 AST/ ALT elevation in 2 pts, one with anal ca and one with vaginal ca. For one patient with grade 3 AST/ALT elevation dose reduction of M9241 from 16.8 to 8 mcg/kg allowed for continued treatment with AST/ ALT remaining at grade 1 or less. One additional patient had transient asymptomatic grade 4 neutrope- nia. No other treatment related grade 3 or greater toxicities were noted. 10/14 (71%) pts have had ob- jective responses: 1 CR (anal ca) and 9 PRs (3 cervical, 2 vulvar/vaginal, 2 anal, 2 oropharyngeal) with 9/10 of these responses ongoing after a median 5 month of follow up. Of the 14 pts, 6 pts have check- point nave disease and 8 pts have checkpoint refractory disease. 5/6 (83%) pts with checkpoint nave disease and 5/8 (63%) pts with checkpoint refractory disease have had objective responses. Analyses of immune responses and other immune correlates are ongoing. Conclusions: Triple combination of PDS0101, M9241 and bintrafusp alfa appears to have a manageable safety profile along with early evi- dence of notable clinical activity for pts with both checkpoint nave as well as checkpoint refractory HPV 16+ advanced malignancies. Clinical trial information: NCT04287868. Research Sponsor: U.S. Na- tional Institutes of Health, Pharmaceutical/Biotech Company. © 2021 by American Society of Clinical Oncology. Visit abstracts.asco.org and search by abstract for disclosure information. DEVELOPMENTAL THERAPEUTICS—IMMUNOTHERAPY 2502 Oral Abstract Session First report of the safety/tolerability and preliminary antitumor activity of HB-201 and HB- 202, an arenavirus-based cancer immunotherapy, in patients with HPV16+ cancers. Alan Loh Ho, Marshall R. Posner, Jiaxin Niu, Siqing Fu, Rom S. Leidner, Alexander T. Pearson, Ki Y. Chung, Debra L. Richardson, Ding Wang, Agustin Pimentel, Jorge J. Nieva, Ari Rosenberg, Bharat Burman, Corinne Iacobucci, Xiaoping Qing, Andy Hwang, Kia Katchar, Katia Schlienger, Igor Matushansky, David G. Pfister; Memorial Sloan Kettering Cancer Center, New York, NY; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY; Banner MD Anderson Cancer Center, Gilbert, AZ; The University of Texas MD Anderson Cancer Center, Houston, TX; Earle A. Chiles Research Institute at Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, OR; Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL; Institute for Translational Oncology Research, Prisma Health-Upstate Cancer Institute, Greenville, SC; Stephen- son Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City, OK; Henry Ford Hospital, Detroit, MI; University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; University of Southern California, Los Angeles, CA; University of Chicago, Chicago, IL; Hookipa Pharma Inc., New York, NY Background: Human papillomavirus 16 (HPV16) is linked to several cancer types. Treatment options are limited for patients with HPV16 positive (HPV16+) recurrent or metastatic cancers. Generation and maintenance of HPV16+ malignant state require stable expression of HPV16-specific E7 and E6 onco- proteins, also a source of immunogenic neoantigens. HB-201 and HB-202 are replicating live-attenuat- ed vectors based on lymphocytic choriomeningitis virus and Pichinde virus, respectively, which express the same non-oncogenic HPV16 E7E6 fusion protein to induce tumor-specific T-cell responses.
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