Bruckner Howard W, Chawla Sant P, Omelchenko Nadezhda, Brigham Don A, Gordon Erlinda M
Bruckner Oncology, New York, NY, United States.
Cancer Center of Southern California, Santa Monica, CA, United States.
Front Mol Med. 2023 May 18;3:1105680. doi: 10.3389/fmmed.2023.1105680. eCollection 2023.
Metastatic breast cancer is associated with a poor prognosis and therefore, innovative therapies are urgently needed. Here, we report on the results of a Phase I-II study using DeltaRex-G for chemotherapy resistant metastatic carcinoma of breast. Dose limiting toxicity; Antitumor activity. : ≥18 years of age, pathologic diagnosis of breast carcinoma, adequate hematologic and organ function. : Dose escalation of DeltaRex-G 1-4 x 10cfu intravenously thrice weekly x 4 weeks with 2-week rest period. Treatment cycles repeated if there is ≤ Grade 1 toxicity until disease progression or unacceptable toxicity. NCI CTCAE v3 for adverse events reporting, vector related testing. RECIST v1.0, International PET criteria and Choi criteria for response, progression free and overall survival. Twenty patients received escalating doses of DeltaRex-G from 1 × 10 cfu to 4 × 10 cfu thrice weekly for 4 weeks with a 2-week rest period. : ≥ Grade 3 treatment-related adverse event: pruritic rash ( = 1), no dose limiting toxicity, no replication-competent retrovirus, nor vector-neutralizing antibodies detected. No vector DNA integration was observed in peripheral blood lymphocytes evaluated. : by RECIST v1.0: 13 stable disease, 4 progressive disease; tumor control rate 76%; by PET and Choi Criteria: 3 partial responses, 11 stable disease, 3 progressive disease; tumor control rate 82%. Combined median progression free survival by RECIST v1.0, 3.0 months; combined median overall survival, 20 months; 1-year overall survival rate 83% for Dose Level IV. Biopsy of residual tumor in a participant showed abundant CD8 killer T-cells and CD45 macrophages suggesting an innate immune response. Two patients with pure bone metastases had >12-month progression free survival and overall survival and are alive 12 years from the start of DeltaRex-G therapy. These patients further received DeltaRex-G + DeltaVax for 6 months. Taken together, these data indicate that 1) DeltaRex-G has a distinctively high level of safety and exhibits anti-cancer activity, 2) PET/Choi provide a higher level of sensitivity in detecting early signs of tumor response to DeltaRex-G, 3) DeltaRex-G induced 12- year survival in 2 patients with pure bone metastases who subsequently received DeltaVax immunotherapy, and 4) DeltaRex-G may prove to be a biochemical and/or immune modulator when combined with other cancer therapy/immunotherapy.
转移性乳腺癌预后较差，因此迫切需要创新疗法。在此，我们报告一项I-II期研究的结果，该研究使用DeltaRex-G治疗化疗耐药的转移性乳腺癌。剂量限制毒性；抗肿瘤活性。入选标准：年龄≥18岁，乳腺癌病理诊断，血液学和器官功能正常。给药方案：DeltaRex-G 1-4×10cfu静脉注射，每周三次，共4周，休息2周。若毒性≤1级，则重复治疗周期，直至疾病进展或出现不可接受的毒性。采用NCI CTCAE v3报告不良事件，进行载体相关检测。采用RECIST v1.0、国际PET标准和Choi标准评估疗效、无进展生存期和总生存期。20例患者接受了剂量递增的DeltaRex-G治疗，从1×10cfu到4×10cfu，每周三次，共4周，休息2周。≥3级治疗相关不良事件：瘙痒性皮疹（=1例），无剂量限制毒性，未检测到复制型逆转录病毒和载体中和抗体。在所评估的外周血淋巴细胞中未观察到载体DNA整合。根据RECIST v1.0标准：13例疾病稳定，4例疾病进展；肿瘤控制率76%；根据PET和Choi标准：3例部分缓解，11例疾病稳定，3例疾病进展；肿瘤控制率82%。根据RECIST v1.0标准，联合无进展生存期的中位数为3.0个月；联合总生存期的中位数为20个月；IV剂量组的1年总生存率为83%。一名参与者残留肿瘤的活检显示有大量CD8杀伤性T细胞和CD45巨噬细胞，提示存在先天性免疫反应。两名单纯骨转移患者的无进展生存期和总生存期均超过12个月，自开始使用DeltaRex-G治疗起已存活12年。这两名患者进一步接受了6个月的DeltaRex-G + DeltaVax治疗。综上所述，这些数据表明：1）DeltaRex-G具有显著的高安全性并表现出抗癌活性；2）PET/Choi在检测肿瘤对DeltaRex-G反应的早期迹象方面具有更高的敏感性；3）DeltaRex-G使两名单纯骨转移患者存活了12年，这两名患者随后接受了DeltaVax免疫治疗；4）DeltaRex-G与其他癌症治疗/免疫治疗联合使用时可能被证明是一种生化和/或免疫调节剂。
