Abstract
We have previously shown that Salmonella immunotherapy is effective to treat B-cell non-Hodgkin lymphoma (B-NHL) in mice. However, this model involves animals with high tumor burden, whereas in the clinics B-NHL patients are usually treated with chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line therapy prior to immunotherapy. Recently, we have described a NHL-B preclinical model using CHOP chemotherapy to achieve MRD in immunocompetent animals that closely resemble patients’ conditions. In this work, we assessed the efficacy of Salmonella immunotherapy in B-NHL-bearing mice undergoing chemotherapy. Salmonella administration significantly delayed tumor growth and prolonged survival of chemotherapy-treated NHL-bearing animals. Mice receiving the CHOP–Salmonella combined therapy showed increased numbers of tumor-infiltrating leukocytes and a different profile of cytokines and chemokines expressed in the tumor microenvironment. Further, Salmonella immunotherapy in CHOP-treated animals also enhanced NK cells cytotoxic activity as well as induced systemic lymphoma-specific humoral and cellular responses. Chemotherapy treatment profoundly impacted on the general health status of recipient animals, but those receiving Salmonella showed significantly better overall body condition. Altogether, the results clearly demonstrated that Salmonella immunotherapy could be safely used in individuals under CHOP treatment, resulting in a better prognosis. These results give strong support to consider Salmonella as a neoadjuvant therapy in a clinical setting.
Highlights
Non-Hodgkin lymphomas (NHL) are the most frequent hemato-oncological malignancies
We have recently described the feasibility of applying CHOP chemotherapy used in clinics to A20-bearing mice and demonstrated that, albeit its cytotoxic effect, CHOP chemotherapy promoted a pro-inflammatory tumor microenvironment and an immune response that resulted in an extended progression-free survival (PFS) [32]
We demonstrated that Salmonella immunotherapy could be administered to lymphoma-bearing animals that are undergoing chemotherapy treatment without any deleterious effects
Summary
Current treatment for patients is a combination of chemotherapy, radiotherapy, and monoclonal antibodies, such as Rituximab [1] All combined these therapies result in high rates of complete remission; a substantial proportion of patients relapse with chemoresistant disease. Salmonella is a facultative anaerobe bacteria that can replicate and accumulate in the tumor microenvironment, which offers the potential to amplify the therapeutic effect at the Salmonella Immunotherapy against NHL tumor site, avoiding toxicity in surrounding tissues [8,9,10]. Salmonella efficiency can be seen as the result of a dual effect, a direct tumoricidal activity [13, 14] and the result of a strong pro-inflammatory response elicited by the bacteria at the tumor site. Typhimurium) has shown to be highly effective as an agent in many types of cancers in both preclinical and clinical models, with a demonstrated safety profile [18]
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