Department of Medicine, Division of Hematology & Oncology, University of California, Los Angeles, CA, USA.
J Immunother. 2012 Sep;35(7):534-43. doi: 10.1097/CJI.0b013e318261e679.
Rituximab plus chemotherapy is standard therapy for patients with non-Hodgkin B cell lymphoma, but often complete response or cure is not achieved. Toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG) can improve antibody-dependent cellular cytotoxicity and adaptive antitumor immune responses. Using a syngeneic murine B cell lymphoma expressing human CD20 (38C13-huCD20), we previously demonstrated that rituximab plus intratumoral CpG, but not systemic CpG, could eradicate up to half of 7-day established 38C13-huCD20 tumors. However, larger 10-day established tumors could not be cured with this regimen. We thus hypothesized that cytoreduction with cyclophosphamide (Cy) before immunotherapy might permit eradication of these more advanced tumor burdens. Pretreatment with Cy resulted in tumor eradication from 83% of animals treated with rituximab/CpG, whereas Cy/CpG or Cy/rituximab treatments only cured 30% or 17%, respectively (P<0.005). Tumor eradication depended on natural killer cells, but not T cells, macrophages, or complement. Only mice treated with Cy/rituximab/CpG partially resisted rechallenge with tumor cells. Foxp3 Treg and CD11bGr1 myeloid suppressor cells persisted within lymphoid organs after therapy, possibly influencing the ability to establish adaptive tumor immunity. In conclusion, cytoreduction with Cy permitted the cure of large, established lymphomas not otherwise responsive to rituximab plus intratumoral CpG immunotherapy.
利妥昔单抗联合化疗是治疗非霍奇金 B 细胞淋巴瘤患者的标准疗法，但通常无法实现完全缓解或治愈。 Toll 样受体 9 激动剂 CpG 寡脱氧核苷酸（CpG）可以改善抗体依赖性细胞毒性和适应性抗肿瘤免疫反应。我们之前使用表达人 CD20 的同种异体鼠 B 细胞淋巴瘤（38C13-huCD20）进行研究，证明利妥昔单抗联合肿瘤内 CpG，但不联合全身 CpG，可清除多达一半的 7 天建立的 38C13-huCD20 肿瘤。然而，这种方案无法治愈更大的 10 天建立的肿瘤。因此，我们假设在免疫治疗前用环磷酰胺（Cy）进行细胞减灭可能允许清除这些更晚期的肿瘤负担。用 Cy 预处理可使 83%用利妥昔单抗/CpG 治疗的动物中的肿瘤完全消除，而 Cy/CpG 或 Cy/利妥昔单抗治疗仅分别治愈 30%或 17%（P<0.005）。肿瘤消除依赖于自然杀伤细胞，但不依赖于 T 细胞、巨噬细胞或补体。只有用 Cy/利妥昔单抗/CpG 治疗的小鼠对肿瘤细胞的再次攻击有部分抵抗力。Foxp3 Treg 和 CD11bGr1 髓样抑制细胞在治疗后仍存在于淋巴器官中，可能影响建立适应性肿瘤免疫的能力。总之，用 Cy 进行细胞减灭可使大的、已建立的淋巴瘤得到治愈，而这些淋巴瘤对利妥昔单抗联合肿瘤内 CpG 免疫治疗无反应。
