Combination of Cyclophosphamide, Rituximab, and Intratumoral CpG Oligodeoxynucleotide Successfully Eradicates Established B cell Lymphoma

Abstract

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.

A TLR7 agonist enhances the antitumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells

“…26 Whereas the antitumor efficacy of rituximab has previously been enhanced by intra-tumoral administration of the TLR9 agonist CpG, systemic administration of CpG was not effective and as a result only local tumor control secondary to local administration was seen. 27, 28 In this model, NK cells were again shown to be the major effector cell with no apparent role for T cells or macrophages: no loss of therapy was seen in clodronate-liposome-treated mice. However, when a CpG oligonucleotide 1018 ISS was combined with rituximab subcutaneously in a phase II clinical trial the response rate was similar to that reported for rituximab alone.…”

Heterogeneity of Toll-like receptor 9 signaling in B cell malignancies and its potential therapeutic application

“…Furthermore, rituximab plus intratumoral CpG ODNs, but not systemic CpG ODNs, eradicate up to half of 7-day established 38C13-huCD20 tumors, a syngeneic murine B cell lymphoma expressing human CD20. Additionally, brief and extended-duration administration of CpG 7909 in combination with rituximab has been found to be safe in patients with relapsed/refractory non-Hodgkin lymphoma [ 96 ].…”

Intratumoral gene therapy versus intravenous gene therapy for distant metastasis control with 2-Diethylaminoethyl-Dextran Methyl Methacrylate Copolymer Non-Viral Vector–p53

“…42,48,49,[73][74][75][76] Additional methods of enhancing the intratumoral gene therapy have been previously performed with the addition of radiotherapy, chemotherapy, thermal ablation, sorafenib, imatinib, use of ultrasound system, rituximab and dendritic cells to gene therapy administration alone. 34,[77][78][79][80][81][82] In our current study, we used the novel non-viral vector DDMC as the vehicle for the local intratumoral administration of pSicop53. The DDMC was synthesized by graft polymerization of methyl methacrylate (MMA) onto 2-Diethylaminoethyl-Dextran Methyl Methacrylate Copolymer (DAEX).…”