Potential Approaches Versus Approved or Developing Chronic Myeloid Leukemia Therapy

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, continued use of these inhibitors has contributed to the increase in clinical resistance and the persistence of resistant leukemic stem cells (LSCs). So, there is an urgent need to introduce additional targeted and selective therapies to eradicate quiescent LSCs, and to avoid the relapse and disease progression. Here, we focused on emerging BCR-ABL targeted and non-BCR-ABL targeted drugs employed in clinical trials and on alternative CML treatments, including antioxidants, oncolytic virus, engineered exosomes, and natural products obtained from marine organisms that could pave the way for new therapeutic approaches for CML patients.

Recombinant adeno-associated viruses as a gene delivery vehicle for the use in molecular medicine

Breast cancer (BC) is a cancer with a high prevalence and mortality among women worldwide. With the current diagnostics methods, BC may remain undetected at its early stages, and the therapies developed for the disease are associated with severe side effects. Oncolytic viruses can be the basis of the new, effective BC treatment approaches. The viruses destroy tumor cells directly and launch the antitumor immune response; this dual action supports their efficacy. It is possible to make the oncolytic virus therapy more effective by designing genetically modified viruses that can target BC cells better and/or induce a stronger antitumor immune response. This review outlines the directions of development of oncolytic viruses in BC treatment, covers the optimal ways of delivering viruses to the tumor and the efficacy of their use in combination with other therapeutic agents (methods) and presents the prospects of using oncolytic viruses in antitumor vaccines.

The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors

While many classes of chemotherapeutic agents exist to treat solid tumors, few can generate a lasting response without substantial off-target toxicity despite significant scientific advancements and investments. In this review, the paths of development for nanoparticles, oncolytic viruses, and oncolytic bacteria over the last 20 years of research towards clinical translation and acceptance as novel cancer therapeutics are compared. Novel nanoparticle, oncolytic virus, and oncolytic bacteria therapies all start with a common goal of accomplishing therapeutic drug activity or delivery to a specific site while avoiding off-target effects, with overlapping methodology between all three modalities. Indeed, the degree of overlap is substantial enough that breakthroughs in one therapeutic could have considerable implications on the progression of the other two. Each oncotherapeutic modality has accomplished clinical translation, successfully overcoming the potential pitfalls promising therapeutics face. However, once studies enter clinical trials, the data all but disappears, leaving pre-clinical researchers largely in the dark. Overall, the creativity, flexibility, and innovation of these modalities for solid tumor treatments are greatly encouraging, and usher in a new age of pharmaceutical development.

EXTH-56. ZIKA VIRUS TREATMENT SIGNIFICANTLY PROLONGS SURVIVAL IN A GLIOBLASTOMA PATIENT DERIVED XENOGRAFT MODEL

The poor median survival for patients with glioblastoma (GBM) of 15 months has not budged for the past 15 years, when the current standard treatment was first approved. There is no standard of care chemotherapy for recurrent GBM. We previously showed that Zika virus (ZIKV) tropism for GBM cells is mediated through the receptor tyrosine kinase, AXL. This infection is cytotoxic. In this study we show that ZIKV is an effective oncolytic virus in a patient derived xenograft model. Fox N1 Nude homozygous female mice 6-8-weeks-old were grouped into 4 experimental arms: two patient derived cell lines, each with a ZIKV treated and a control group. There were 12 mice in each arm. Animals received subcutaneous flank injections of GBM 8049 or its AXL CRISPR knockout 8049 AXLKO (2x106 cells). When tumors reached 200 mm3, mice received intra-tumoral injection of 2.5x106 ZIKV particles or saline. ZIKV induced complete tumor remission in 22 of 24 animals (8049: 11/12; 8049 AXLKO: 11/12). There was no tumor remission in the saline treated animals. Median survival of 8049 and 8049 AXLKO ZIKV treated mice was 124 days and 125 days, respectively. This is compared to median survival of control animals 8049: 42 days; 8049 AXLKO: 46 days (P= 0.001). Among ZIKV treated mice, there were two recurrences: one in the 8049 tumor (24 days after significant tumor remission) and one 8049 AXLKO tumor (7 days after significant tumor remission). We conclude that ZIKV should be considered a candidate oncolytic virus for GBM.

381 Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study

BackgroundIntratumoral administration of V937, a bioselected genetically unmodified Coxsackievirus A21, has shown antitumor activity both as a monotherapy and in combination with the anti–PD-1 antibody pembrolizumab.1–3 V937 induces lytic tumor cell infection and upregulation of members of immune checkpoint pathways.2 We present the results from the phase 1b MITCI study that evaluated V937 plus ipilimumab for advanced melanoma.MethodsEligible patients had unresectable or metastatic stage IIIB/C or IV melanoma amenable to intratumoral injection. Patients received intratumoral V937 3×108 TCID50 on days 1, 3, 5, 8, and 22, then Q3W for 14 more injections plus intravenous ipilimumab 3 mg/kg Q3W administered 4 times starting on day 22. Imaging was done Q6W beginning at day 106; response was assessed per immune-related response criteria (irRC). The primary endpoints were safety and ORR in the overall population and in patients whose disease progressed on prior anti–PD-1 therapy.Results50 patients were enrolled and received ≥1 dose of study treatment. At data cutoff (February 21, 2020), all had discontinued the study and study therapy. Median (range) age was 64.5 (28–88) years. Fourteen patients (28%) had stage III disease. Forty patients (80%) had received prior systemic treatment, 33 of whom had received anti–PD-1 therapy. The median number of cycles of ipilimumab was 4 (range, 1–4), and the number of intratumoral injections of V937 was 9 (range, 5–19). Among the 94% of patients who had ≥1 treatment-related AE, 14% had grade 3/4 treatment-related AEs, none of which were considered related to V937. The most common grade 3/4 treatment-related AEs were dehydration, diarrhea, and hepatotoxicity (4% each). No grade 5 treatment-related AEs occurred. The most common treatment-related AEs were pruritus (50%), fatigue (44%), diarrhea (32%), and nausea (22%). Efficacy outcomes for the overall population and by prior anti-PD-1 therapy use are presented in table 1. Tumor regression was observed in injected and noninjected lesions.Abstract 381 Table 1ConclusionsV937 plus ipilimumab was safe and the toxicities were manageable and consistent with that anticipated for the individual treatment components. ORR was robust and significantly higher than anticipated with ipilimumab monotherapy, including in patients who had received prior anti–PD-1 therapy. Most responses were durable (≥26 weeks), and responses seen in noninjected metastases provided evidence of probable systemic immune activation. The combination of V937 plus ipilimumab warrants further investigation in a larger trial in patients with advanced melanoma.AcknowledgementsMedical writing assistance was provided by Kathleen Estes, PhD, of ICON plc (North Wales, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationNCT02307149ReferencesPandha H, Harrington K, Ralph C, Melcher A, Gupta S, Akerley W, et al. Abstract CT115: phase 1b KEYNOTE 200 (STORM study): a study of an intravenously delivered oncolytic virus, coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients. Cancer Res 2017;77(13 suppl):CT115.Andtbacka RHI, Curti BD, Kaufman H, Nemunaitis JJ, Daniels GA, Hallmeyer S, et al. Dynamics of tumor response in advanced melanoma patients treated with coxsackievirus A21. J Clin Oncol 2016;34(15 suppl):9553.Silk AW, Kaufman H, Gabrail N, Mehnert J, Bryan J, Norrell J, et al. Phase 1b study of intratumoral coxsackievirus A21 (CVA21) and systemic pembrolizumab in advanced melanoma patients: interim results of the CAPRA clinical trial. Cancer Res 2017;77(13 suppl):CT026.Ethics ApprovalAn independent institutional review board or ethics committee approved the protocol at each study site, and the trial was conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients provided informed consent.