Our understanding of the interaction between the host immune system and cancer has evolved rapidly over the previous 10 years due to the clinical success induced by checkpoint inhibition. Previous immunologic work can now be realized in combination strategies. Modified Vaccinia Ankara (MVA) offers significant opportunities due to its natural induction of innate and adaptive immunity, large payload, and excellent safety profile.
MVA vectors were administered subcutaneously (SC), intravenously (IV) or intratumorally (IT) into tumor-bearing mice. Cytokine secretion profile in serum was assessed by Luminex analysis. NK and T cell infiltration and activation in various organs and cytolytic activity against target cells were determined by flow cytometry-based assays. PD-1 immune checkpoint blockade (ICB), low dose cyclophosphamide, tumor-targeting Abs or 15 Gy radiotherapy were administered along with IV MVA.
Recombinant MVA (rMVA) in which tumor antigens and costimulatory molecules are encoded can be customized for maximal effect by route of administration. rMVA administered intravenously (IV) causes superior induction of antigen specific T cells, cytokines and NK cells than previously seen with subcutaneous or intramuscular routes. Encoding CD40L in addition amplifies the effects and efficacy improves in relevant models. This is dependent on T cells and NK cells, indicating a potential solution to one tumor-resistance mechanism, MHC loss and/or mutation. Furthermore, the combination of rMVA with tumor targeting antibodies, checkpoint inhibition, radiotherapy or chemotherapy often showed additional synergistic therapeutic effects. Administration of MVA alone intratumorally (IT) causes innate immune activation through toll like receptors (TLRs) as well as the cGAS / STING pathway. Recombinant antigen encoding rMVA improves systemic and local antigen-specific T cell responses. These effects can be bolstered by encoding certain costimulatory molecules.
IV and IT recombinant MVA may offer off the shelf solutions to resolve many of the host – tumor immunity interactions that result in lack of efficacy of checkpoint inhibition alone in most patients. Bavarian Nordic plans to initiate clinical trials with existing agents in 2019 applied IV and IT and will create novel constructs to maximize clinical effect, planned to initiate in 2020 and beyond.
Bavarian Nordic, Inc.
Bavarian Nordic, Inc.
C. Heery: Employee and shareholder: Bavarian Nordic, Inc. C. Pico-Navarro, T. Adams, L. Bauman, J. Medina, M. Hinterberger, A. Heiseke, H. Lauterbach, H. Hochrein: Employee of Bavarian Nordic.
Prostate cancer patients with distant metastasis have poor prognosis and develop resistance to all standard drugs at various time intervals. Therapeutic options which can alleviate symptoms and prolong survival are required for these patients. [177Lu]prostate-specific membrane antigen ([177Lu]PSMA) is a novel drug based on a theranostic concept. Here, we have presented the safety and efficacy profile of one cycle of [177Lu]PSMA in metastatic castration-resistant prostate cancer (mCRPC) patients who have exhausted all standard therapeutic options.
Twenty two patients treated with at least first line anti-androgens and docetaxel were treated with one cycle of [177Lu]PSMA therapy on a compassionate basis. Haemoglobin, total leukocyte counts, platelets and serum creatinine for toxicity profile while prostate specific antigen (PSA), Eastern Cooperative Oncology Group (ECOG) performance status, visual analogue scale (VAS) and analgesic quantification scale (AQS) for therapeutic efficacy were recorded pre and 8 weeks post therapy. Wilcoxon signed-rank and ANOVA tests were used for statistical analysis.
Partial response (PR), stable disease (SD) and progressive disease (PD) for PSA were seen in 5 (22.7%), 13 (59.1%) and 4 (18.2%) patients, respectively, treated with mean 6.88GBq dose of [177Lu]PSMA. 8/22 (36.4%) patients showed ≥ 30% drop in PSA. Grade 3 haemoglobin toxicity was seen in 5/22 (22.7%) patients. No patient developed grade 4 haemoglobin toxicity. No patients had grade 3 or 4 leukocytopenia or thrombocytopenia. Wilcoxon signed-rank test showed statistically significant (p < 0.05) difference in pre- and post-treatment ECOG, VAS, AQS scores while it was not significant for PSA (P > 0.05). ANOVA test showed a statistically significant difference in mean doses of [177Lu]PSMA used in the three PSA response groups while the difference was non-significant for other variables.
We conclude that [177Lu]PSMA therapy delivers adequate pain palliation in all end-stage mCRPC patients and it has a potential to become an effective therapeutic option in properly selected patients.
Manoj Gupta.
Has not received any funding.
All authors have declared no conflicts of interest.
Insufficient information is available on cancer types among patients enrolled in all-comer phase I oncology trials. We evaluated the global trends in cancer types of patients in these trials, including time-dependent changes and regional differences among North America, Europe, and Asia.
The PubMed database was searched to identify single-agent phase I trials published between 1991 and 2015, which enrolled patients with any type of solid tumor. The inclusion and exclusion criteria were predefined for article selection; trials recruiting from specific patient populations were excluded from the analysis.
We identified 866 eligible clinical trials, which enrolled a total of 29,112 patients with advanced solid tumors. The selected trials were conducted mainly in North America (55.5%), Europe (27.8%), and Asia (10.5%). The distribution of cancer types in phase I trials was considerably different from cancer-related incidence and mortality. Colorectal cancers (n = 7,510, 25.8%) were the most prevalent in phase I trials, followed by lung cancer (n = 3,212, 11.0%), sarcoma (n = 1,756, 6.0%), breast cancer (n = 1,623, 5.6%), renal cancer (1589, 5.5%), and ovarian cancer (1473, 5.1%). The proportion of patients with either colorectal or lung cancer decreased with time. The proportion of trials, in which patients with either of these two cancers accounted for ≥50% of the total enrolled patients in each trial, had also decreased as follows: 31/67 trials (46.3%) from 1991 to 1995, 58/142 (40.8%) from 1996 to 2000, 59/223 (26.5%) from 2001 to 2005, 38/189 (20.1%) from 2006 to 2010, and 41/245 (16.7%) from 2011 to 2015. These trends were consistent across the three regions, with an increase in the proportion of various types of cancer enrolled in phase I trials.
The distribution of cancer types among patients enrolled in all-comer phase I trials has changed dramatically. Patients with common types of cancer, with poor general condition and vital organ dysfunction after multiple lines of therapy, are likely not to participate in phase I trials.
Noboru Yamamoto.
Has not received any funding.
T. Shimizu: Consulting: Takeda Oncology; Honoraria: ONO, ONO Pharma Taiwan, Boehringer Ingelheim, Taiho, Chugai; Research funding: Takeda Oncology, PharmaMar, BMS Japan, Daiichi Sankyo, SymBio, Five Prime Therapeutics, 3D Medicine. S. Kondo: Research funding: AstraZeneca, Eli Lilly, Pfizer. Y. Fujiwara: Consulting: ONO, BMS Japan; Participation in speakers’ bureau: ONO, BMS Japan, MSD, Taiho; Research funding: AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Lilly Japan, Novartis, BMS Japan, MSD, Merck Serono, Abbvie, Incyte. N. Yamamoto: Consulting: Eisai, Takeda, Otsuka, OncoTherapy; Speakers’ bureau: BMS, Pfizer, AstraZeneca, Lilly, ONO, Chugai; Funding: Chugai, Taiho, Eisai, Quintiles, Astellas, Novartis, Daiichi Sankyo, Boehringer, Takeda, Kyowa Kirin, Bayer, Pfizer, BMS, ONO.