Cure of mice bearing a late-stage, highly metastatic, drug-resistant tumor by adoptive chemoimmunotherapy

Abstract

We show here that in contrast to BALB/c mice bearing a late-stage, large MOPC-315 plasmacytoma, BALB/c mice bearing a late-stage, large RPC-5 plasmacytoma were not cured by cyclophosphamide therapy (15, 50, 100 or 200 mg/kg). However, most BALB/c mice bearing a late-stage RPC-5 tumor were cured by cyclophosphamide therapy (100 mg/kg) in conjunction with adoptive immunotherapy using tumor-infiltrated spleen cells (TISpC) that had been cultured with inactivated RPC-5 tumor cells plus polyethylene glycol 6000, even though this protocol was not effective for the therapy of mice bearing a barely palpable, early-stage RPC-5 tumor. Only a few of the mice that were cured of a late-stage RPC-5 tumor following adoptive chemoimmunotherapy (ACIT) were resistant to a subsequent challenge with RPC-5 tumor cells. However, the challenged mice that had developed progressively growing tumors could then be cured by cyclophosphamide alone when the tumor became large, even though this treatment was not curative for mice bearing a tumor of similar size but not previously treated by ACIT. Thus, the cure by ACIT of BALB/c mice bearing a lethal, late-stage RPC-5 tumor with extensive metastases provides a novel experimental tumor model for investigating the mechanisms by which a chemotherapeutic drug and adoptive cellular immunotherapy can cooperate in causing the complete regression of a large tumor load.

Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice.

“…In conclusion, our data strongly suggest that CTX induces release of soluble factors that can enhance the proliferation, differentiation, and activity of tumor-specific immune T cells. These results could lead to a general reinterpretation of the synergistic effects of CTX and immunotherapy observed by others in experimental models (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), generally assumed to be mediated by effects on suppressor T cells. The data reported in this article may have more general implications on the relationships between the homeostatic mechanisms generated as a consequence of events perturbing the lymphohemopoietic equilibrium and the survival, expansion, and differentiation of immune cells endowed with a given T cell repertoire.…”

“…Moreover, an ensemble of experiments indicated that an intact immune system of the recipient host and some soluble factors (IFN-␣ / ␤ ) were essential in mediating the antitumor response to the adoptive immunotherapy in the CTX-injected animals. Altogether, these results may lead to reinterpretation of the mechanisms underlying the synergistic effects of CTX and adoptive immunotherapy observed in various experimental tumor models by others (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), largely explained on the assumption of a selective effect of CTX on "suppressor T cells" (24,(26)(27)(28).…”

“…Several reports have shown a strong synergistic effect of combined therapy with CTX and immune T cells in inhibiting tumor growth in mice (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), and a few clinical trials are currently in course with cancer patients using similar chemoimmunotherapeutic strategies (29-31). In this study, we have provided additional data on the powerful antitumor activity that can be generated after a combined CTX/immunotherapy regimen in mice transplanted with four syngeneic tumors, exhibiting a different response to CTX alone.…”

“…Cyclophosphamide (CTX) 1 is a widely used chemotherapeutic agent in cancer therapy (for review see reference 7). CTX has also been used by several groups as an immunomodulatory agent against murine and human tumors (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Many studies have reported that CTX can increase the efficacy of immunotherapeutic regimens by removing tumor-induced suppressor T cells (23)(24)(25)(26)(27)(28).…”

Antitumor reactivity induced by liposomal MTP-PE in a liver metastasis model of colon cancer in the rat

“…We did not specifically aim to optimize the treatment schedule in the present study. Nevertheless, increased efficacy of liposomal muramyl peptides is likely to result from combination with, for instance, chemotherapy [29][30][31]. Also, efficacy may be improved when using an alternating treatment schedule with immunomodulators triggering different macrophage activating pathways, thus preventing the effector cells becoming refractory to subsequent stimulation [32].…”