Abstract
Combination chemotherapy is often employed to improve therapeutic efficacies of drugs. However, traditional combination regimens often utilize drugs at or near‐their maximum tolerated doses (MTDs), elevating the risk of dose‐related toxicity and impeding their clinical success. Further, high doses of adjuvant or neoadjuvant chemotherapies can cause myeloablation, which compromises the immune response and hinders the efficacy of chemotherapy as well as accompanying treatments such as immunotherapy. Clinical outcomes can be improved if chemotherapy combinations are designed to reduce the overall doses without compromising their therapeutic efficacy. To this end, we investigated a combination of camptothecin (CPT) with doxorubicin (DOX) as a low‐dose treatment option for breast cancer. DOX‐CPT combinations were synergistic in several breast cancer cell lines in vitro and one particular ratio displayed extremely high synergy on human triple negative breast cancer cells (MDA‐MB‐231). This combination led to excellent long‐term survival of mice bearing MDA‐MB‐231 tumors at doses roughly five‐fold lower than the reported MTD values of its constituent drugs. Impact of low dose DOX‐CPT treatment on local tumor immune environment was assessed in immunocompetent mice bearing breast cancer (4T1) tumors. The combination was not only superior in inhibiting the disease progression compared to individual drugs, but it also generated a more favorable antitumor immunogenic response. Engineering DOX and CPT ratios to manifest synergy enables treatment at doses much lower than their MTDs, which could ultimately facilitate their translation into the clinic as a promising combination for breast cancer treatment.
Highlights
Combination chemotherapy, in spite of its limitations, is the current gold standard for the treatment of advanced breast cancers.[1,2] A meta-analysis of several combination therapies for the treatment of metastatic breast cancer revealed that a heterogeneous yet statistically significant benefit was obtained for combination regimens in terms of tumor progression and overall survival.[3]
There is a growing consensus on combining chemotherapy drugs at specific molar ratios to afford higher potency and yield effective responses at greatly diminished drug doses, their impact on the intratumoral immune response is rarely assessed. We propose one such low dose therapy using two topoisomerase inhibitors, doxorubicin (DOX) and camptothecin (CPT), for the effective management of an aggressive triple negative breast cancer and study its effect on the intratumoral immune microenvironment
The highest synergy was observed at a molar ratio of 1:1 (DOX:CPT), which corresponded to a combination treatment that achieved similar efficacies at significantly reduced doses compared to their single drug counterparts
Summary
Combination chemotherapy, in spite of its limitations, is the current gold standard for the treatment of advanced breast cancers.[1,2] A meta-analysis of several combination therapies for the treatment of metastatic breast cancer revealed that a heterogeneous yet statistically significant benefit was obtained for combination regimens in terms of tumor progression and overall survival.[3] Notwithstanding these improvements, the median survival times in combination treatment are still low and the survival benefits are counterbalanced with a proportional increase in the toxicity contributing to severe morbidity and poor quality of life for patients This is because combination chemotherapies typically employ delivery of their components at their maximum tolerated doses (MTDs) under the assumption that they have nonoverlapping toxicities.[4,5] in the clinic, patients are simultaneously exposed to near toxic doses of multiple poorly tolerable agents that manifest increased adverse effects and eventually undermine the intended therapeutic benefit. We show that, when combined, the drug doses used in this study can elicit an effective antitumor immune effect in a syngeneic breast cancer model
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