Downloaded from http://journals.lww.com/immunotherapy-journal by BhDMf5ePHKbH4TTImqenVBosEKX31uF96LySho9svi1nhqC30p8cHTXw00Yx+82FJo5jqbdMDpA= on 10/25/2020 A Phase I, Open-label, Dose-escalation, and Cohort Expansion Study to Evaluate the Safety and Immune Response to Autologous Dendritic Cells Transduced With AdGMCA9 (DC-AdGMCAIX) in Patients With Metastatic Renal Cell Carcinoma Izak Faiena,* Begoña Comin-Anduix,† Beata Berent-Maoz,‡ Adrian Bot,§ Nazy Zomorodian,* Ankush Sachdeva,* Jonathan Said,∥ Gardenia Cheung-Lau,† Jia Pang,‡ Mignonette Macabali,‡ Thinle Chodon,¶ Xiaoyan Wang,# Paula Cabrera,‡ Paula Kaplan-Lefko,‡ Karim Chamie,* Arie S. Belldegrun,* Allan J. Pantuck,* and Alexandra Drakaki*∥ Summary: Expression of carbonic-anhydrase IX (CAIX) in clear cell renal cell carcinoma (RCC) makes it an attractive vaccine target. We developed a fusion-gene construct, granulocyte- macrophage (GM) colony-stimulating factor+CAIX, delivered by an adenoviral vector (Ad) into autologous dendritic cells (DCs) in this phase 1 study. The injected immature DCs were expected to stimulate an antigen-specific immune response against CAIX expressing RCC. Three dose-escalation cohorts (5, 15, and 50×10 6 cells/administration) were injected intradermally q2wk×3 doses based on a 3+3 design. The primary objective was the safety of the injections. Secondary objec- tives were immune responses using enzyme-linked immunosorbent spot, a serum biomarker panel, and clinical response. Fifteen patients with metastatic RCC were enrolled, and 9 patients received all 3 doses. No serious adverse events were seen. There were 3 (33%) patients with grade 1 fatigue, 1 of whom subsequently experienced grade 2 fatigue. One patient (11%) experienced grade 1–2 leukopenia. Only 1 patient (11%) experienced grade 2 flu-like symptoms. Of the 9 patients who received treatment, 1 expired of progressive disease, 2 patients were lost to follow-up and 6 patients are alive. Of the 6 patients, 5 have progressive disease, and 1 has completed treatment with stable disease at 27 months follow-up. Immune response meas- urements appeared more robust in higher dose cohorts, which appeared to be related to patients with stable disease at 3 months. These early data show that autologous immature DC-AdGMCAIX can be safely given to metastatic RCC patients without any serious adverse events with CAIX-specific immune response elicited by the treatment. These preliminary data support further study of Ad- GMCAIX, particularly with combination therapies that may enhance clinical activity. Key Words: cancer vaccine, dentritic cells, metastatic renal cell carcinoma, immunotherapy (J Immunother 2020;43:273–282) S ignificant progress in the understanding of the biology of renal cell carcinoma (RCC) and the approval of new immuno-oncologic agents for metastatic renal cell carci- noma (mRCC) expanded the treatment armamentarium for second-line options in patients who progress on targeted therapy. 1 In addition, as patients are benefiting from these treatments, a recent expansion to the frontline setting have shifted the standard of care. 2 Despite the efficacy of targeted and immune-related therapies, durable clinical responses are absent for the majority of patients. However, these treat- ments will still eventually fail some patients requiring con- tinued effort to develop novel drugs across all lines of therapy for mRCC. Carbonic-anhydrase IX (CAIX) is a hypoxia-inducible tumor antigen that is significantly expressed in many epi- thelial tumors, including RCC. 3–5 CAIX is a cell surface enzyme, which is crucial to a wide variety of processes such as pH regulation and is associated with tumor cell survival in hypoxic conditions. 6 CAIX expression in normal tissues is limited and is restricted predominantly to the gastric mucosa, pancreatobiliary epithelium, and proximal bowel crypt bases. 7 In RCC, inactivation or loss of the von Hippel- Lindau tumor suppressor gene which is the most common alteration in clear cell tumors, leads to constitutive expres- sion of HIF-1a and upregulation of hypoxia-inducible genes, including vascular endothelial growth factor and CAIX. 8 Studies have demonstrated the presence of CAIX epitopes associated with major histocompatibility complex (MHC) class I and class II, which can be recognized by Received for publication March 11, 2020; accepted July 7, 2020. From the *Department of Urology, Institute of Urologic Oncology; ‡Department of Medicine, Division of Hematology and Oncology; ∥Department of Pathology, David Geffen School of Medicine at University of California; †Department of Surgery, Division of Surgical-Oncology, Jonsson Comprehensive Cancer Center University of California Los Angeles and Parker Institute for Can- cer Immunotherapy at UCLA; #Department of General Internal Medicine and Healthy Services Research, University of California Los Angeles, Los Angeles; §Kite Pharma Inc., A Gilead Company, Santa Monica, CA; and ¶Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY. Trial registration: Clinicaltrials.gov, NCT01826877, registered April 4, 2013 (https://clinicaltrials.gov/ct2/show/NCT01826877). All patients gave written informed consent for participation. A.B., B.C.-A., A.J.P., A.D., A.S.B.: designed the study. I.F., A.S., N.Z., A.D., K.C.: treated patients and performed the clinical data acquis- ition. I.F., B.C.-A., J.S., A.D.: performed analysis of the clinical data. I.F., B.C.-A., B.B.-M., G.C.-L., J.P., M.M., P.C., P.K.-L., A.D.: analyzed and interpreted the immune assay. B.C.-A., T.C., B.B.-M., G.C.-L., J.P., M.M., P.C., P.K.L.: contributed to vaccine develop- ment. data. I.F., B.C.-A., A.D.: wrote the manuscript. Reprints: Izak Faiena, 300 Stein Plaza, Suite 331, Los Angeles, CA 90095 (e-mail: ifaiena@gmail.com). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www. immunotherapy-journal.com. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. CLINICAL STUDY J Immunother  Volume 43, Number 9, November/December 2020 www.immunotherapy-journal.com | 273 Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.