Parra Karla, Valenzuela Paloma, Lerma Natzidielly, Gallegos Alejandra, Reza Luis C, Rodriguez Georgialina, Emmenegger Urban, Di Desidero Teresa, Bocci Guido, Felder Mitchell S, Manciu Marian, Kirken Robert A, Francia Giulio
Department of Biological Sciences, University of Texas at El Paso (UTEP), El Paso, TX, USA.
Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
Br J Cancer. 2017 Jan;116(3):324-334. doi: 10.1038/bjc.2016.429. Epub 2017 Jan 5.
Although there are reports that metronomic cyclophosphamide (CTX) can be immune stimulating, the impact of its combination with anti-CTLA-4 immunotherapy for the treatment of cancer remains to be evaluated.
Murine EMT-6/P breast cancer, or its cisplatin or CTX-resistant variants, or CT-26 colon, were implanted into Balb/c mice. Established tumours were monitored for relative growth following treatment with anti-CTLA-4 antibody alone or in combination with; (a) metronomic CTX (ldCTX; 20 mg kg day), b) bolus (150 mg kg) plus ldCTX, or (c) sequential treatment with gemcitabine (160 mg kg every 3 days).
EMT-6/P tumours responded to anti-CTLA-4 therapy, but this response was less effective when combined with bolus plus ldCTX. Anti-CTLA-4 could be effectively combined with either ldCTX (without a bolus), or with regimens of either sequential or concomitant gemcitabine, including in orthotopic EMT-6 tumours, and independently of the schedule of drug administration. Tumour responses were confirmed with CT-26 tumours but were less pronounced in drug-resistant EMT-6/CTX or EMT-6/DDP tumour models than in the parent tumour. A number of tumour bearing mice developed spontaneous metastases under continuous therapy. The majority of cured mice rejected tumour re-challenges.
Metronomic CTX can be combined with anti-CTLA-4 therapy, but this therapy is impaired by concomitant bolus CTX. Sequential therapy of anti-CTLA-4 followed by gemcitabine is effective in chemotherapy-naive tumours, although tumour relapses can occur, in some cases accompanied by the development of spontaneous metastases.
尽管有报道称节拍性环磷酰胺（CTX）具有免疫刺激作用，但其与抗CTLA-4免疫疗法联合用于癌症治疗的影响仍有待评估。
将小鼠EMT-6/P乳腺癌、或其顺铂或CTX耐药变体、或CT-26结肠癌接种到Balb/c小鼠体内。在用单独的抗CTLA-4抗体或与以下药物联合治疗后，监测已形成肿瘤的相对生长情况：（a）节拍性CTX（低剂量CTX；20mg/kg/天），（b）大剂量（150mg/kg）加低剂量CTX，或（c）吉西他滨序贯治疗（每3天160mg/kg）。
EMT-6/P肿瘤对抗CTLA-4治疗有反应，但与大剂量加低剂量CTX联合时，这种反应效果较差。抗CTLA-4可有效地与低剂量CTX（无大剂量）联合，或与吉西他滨序贯或同时给药方案联合，包括原位EMT-6肿瘤，且与给药时间表无关。CT-26肿瘤也证实了肿瘤反应，但在耐药的EMT-6/CTX或EMT-6/DDP肿瘤模型中，反应不如亲本肿瘤明显。许多荷瘤小鼠在持续治疗下发生了自发性转移。大多数治愈的小鼠排斥肿瘤再挑战。
节拍性CTX可与抗CTLA-4治疗联合使用，但这种治疗会因同时使用大剂量CTX而受到损害。抗CTLA-4后序贯吉西他滨治疗在未接受过化疗的肿瘤中有效，尽管可能会发生肿瘤复发，在某些情况下还会伴有自发性转移的发生。
