Effects of Concomitant Medications on Clinical and Immunological Outcomes of Cancer Patients Treated With Oncolytic Adenoviruses
Santeri A. Pakola, Tatiana V. Kudling, Nea Ojala, James H. A. Clubb, Victor Arias, Elise Jirovec, Mirte van der Heijden, Arianna Eleuteri, Lyna Haybout, Susanna Grönberg‐Vähä‐Koskela, Katriina Jalkanen, Tuomo Alanko, Matthew S. Block, Inge Marie Svane, Anna Kanerva, Otto Hemminki, Dafne C. A. Quixabeira, Claudia Kistler, Suvi Sorsa, Victor Cervera‐Carrascon, Akseli HemminkiABSTRACT
Medication taken for other reasons than for the treatment of malignant disease, termed concomitant medication, is known to affect outcomes when used with immune checkpoint inhibitor therapy and other oncological drugs. However, no research in humans has addressed the relationship between concomitant medications and efficacy of oncolytic adenovirus (OAd) therapy. We retrospectively collected medication history of 290 patients enrolled in the Advanced Therapy Access Program (ATAP), an individualized treatment program of OAds. We analyzed associations of different concomitant medications with overall survival and imaging response following therapy. Additionally, to provide further insights into mechanisms using tissue samples, we collected concomitant medication data, tumor transcriptomic data and serum proteomic data from recent Phase I clinical trials with OAd igrelimogene litadenorepvec (Ad5/3‐E2F‐d24‐hTNF‐IRES‐hIL2, TILT‐123). In ATAP, acetaminophen (paracetamol), opium alkaloids, anti‐emetics, proton pump inhibitors, beta blockers, laxatives, and antidepressants use showed a statistical association with shorter overall survival. Use of lipid‐modifying drugs (statins) and thyroid hormones showed a statistical association with better disease control in imaging. In clinical trials with TILT‐123, beta blockers, anti‐emetics, opioids, and benzodiazepines showed a statistical association with shorter overall survival, and lipid‐modifying drugs and thyroid hormones showed a statistical association with improved disease control. Tumor transcriptomic and serum proteomic analysis showed varied temporal and locational effects on inflammatory response varying by drug class. The results provide the first human data suggesting that OAd therapy outcomes might be influenced by concomitant medications. Future studies on mechanisms of reported findings have the possibility of tailoring clinical use of OAds.