Prospective Randomized Phase 2 Trial of Intensity Modulated Radiation Therapy With or Without Oncolytic Adenovirus-Mediated Cytotoxic Gene Therapy in Intermediate-Risk Prostate Cancer

Abstract

Purpose To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. Methods and Materials Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days’) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. Results Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the two arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. Conclusions Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.

Trial Watch—Oncolytic viruses and cancer therapy

“…in combination with cisplatin-based chemoradiation 188,189 (NCT01584284). 190 Moreover, (1) G207 (a conditionally replicating HSV-1 strain) 191 has been tested in combination with radiation therapy in nine patients with progressive, recurrent glioblastoma (NCT00157703); 192 (2) the therapeutic profile of NTX-010 (a native, replication-competent variant of the Seneca Valley picornavirus, also known as SVV-001) 193 in combination with metronomic cyclophosphamide has been assessed in 22 children with neuroendocrine tumors (NCT01048892); 194 (3) Ad5-yCD/mutTKSR39rep-ADP (a replication competent adenoviral strain endowed with superior oncolytic potential) 195 has been tested in combination with intensity modulated radiation therapy 196,197 in 44 prostate carcinoma patients; 198 (4) the clinical activity of HF10 (a replicative HSV-1 strain) 199 has been investigated in 17 subjects with advanced malignancies, who received HF10 intratumorally as standalone immunotherapeutic intervention; 200 (5) MV-NIS (a strain of oncolytic measles virus encoding the human thyroidal sodium iodide symporter), 201,202 has been tested as standalone immunotherapeutic intervention in two myeloma patients; 203 (6) the safety and efficacy of OBP-301 (an oncolytic adenovirus engineered to selectively target telomerase reverse transcriptase (TERT)-overexpressing cells, also known as telomelysin) 204 has been assessed in six elderly subjects with esophageal carcinoma, who received OBP-301 i.t. in combination with radiation therapy (UMIN000010158); 205 and (7) the clinical profile of an oncolytic variant Western Reserve vaccinia virus artificially endowed with improved specificity 206 has been evaluated in 16 individuals with advanced solid malignancies, who were treated with oncolytic virothapy i.t.…”

Short Overview of Clinical Trials With Current Immunotherapeutic Tools for Cancer Treatment

“…Результаты I фазы клинических испытаний по-казали терапевтический потенциал онколитиче-ской терапии (герпесвируса G207) в сочетании с лучевой терапией для лечения злокачествен-ных глиом (NCT00157703) [49]. Была показана эффективность рекомбинантного онколитиче-ского аденовируса в сочетании с лучевой тера-пией для лечения рака простаты (NCT00583492, II фаза) [21]. Проводятся клинические испытания безопасности и эффективности онколитической виротерапии в сочетании с рекомбинантными цитокинами (DNX-2401 + IFNγ, NCT02197169), колониестимулирующими факторами (реови-рус + сарграмостим (GM-CSF), NCT02444546), ингибиторами иммунных контрольных точек -в сочетании с ипилимумаб (NCT02307149) и с пембролизумаб (NCT02565992, NCT02798406, NCT02824965), моноклональными антитела-ми против эндотелиального ростового фактора VEGF (Bevacizumab, NCT01622543) и т.п.…”

Oncolytic adenovirus-mediated therapy for prostate cancer

“…Several adenoviral mutants have proven efficacy in preclinical prostate cancer models, and many of these mutants have later been pursued in early Phase I and Phase II clinical studies by direct intraprostatic injections 56–58. Although evidence of biological activity was reported in combination with radiation and chemotherapy, further improvements in efficacy are needed for patients to be cured 57–61. For example, to target metastatic disease, adenoviral binding to erythrocytes and liver tropism must also be overcome.…”

“…Freytag et al57,61 have systematically modified the dl 1520 virus to generate optimized prostate cancer-selective mutants expressing several cytotoxic factors for a multimodal approach to enhance the effectiveness of radiation therapy in the absence of ADT. For example, the Ad5-CD/TKrep, expressing the chimeric CD/HSV-TK enzyme from the E3 region (Figure 1B), was administered intraprostatically in patients with localized recurrent cancers in combination with systemic delivery of the prodrugs 5-FC and ganciclovir and intensity-modulated radiotherapy (IMRT) in a Phase I trial 103,104.…”

“…A follow-up study 5 years later revealed long-term effectiveness on decreased PSA doubling times 57. A modified, more efficacious version of the same mutant, Ad5-yCD/mutTK(SR39)rep-ADP, employed the yeast CD fused to an improved TK(SR39) mutant enzyme and expressed the adenovirus death protein (ADP) 61. This mutant caused a greater degree of tumor regression in preclinical models 105.…”