Immunotherapy: A useful strategy to help combat multidrug resistance

Abstract

Multidrug resistance (MDR) renders cancer cells relatively invulnerable to treatment with many standard cytotoxic anti-cancer agents. Cancer immunotherapy could be an important adjunct other strategies to treat MDR positive cancers, as resistance to immunotherapy generally is unrelated to mechanisms of resistance to cytotoxic agents. Immunotherapy to combat MDR positive tumors could use any of the following strategies: direct immune attack against MDR positive cells, using MDR as an immune target to deliver cytotoxic agents, capitalization on other immune properties of MDR positive cells, or conditional immunotoxins expressed under MDR control. Additional insights into the immunogenic potential of some cytotoxic agents can also be brought to bear on these strategies. This review will highlight key concepts in cancer immunotherapy and illustrate immune principles and strategies that have been or could be used to help destroy MDR positive tumor cells, either alone or in rational combinations.

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

“…23 Mechanisms underlying chemotherapy-mediated upregulation of the anti-tumor immunity include upregulation of tumor cells immunogenicity, reduction of immune dysfunction by impairing the functionality of immunosuppressive cells, or induction of apoptotic cancer cell death, which activates immune responses. 129 It has been demonstrated that growing tumor cells can be much more sensitive to T-cell attack compared to the quiescent cells. 26 Therefore, chemotherapy could potentiate the efficiency of immunotherapy, at least in part, by stimulating compensatory tumor cell proliferation.…”

“…For example, maximum tolerated doses of cyclophosphamide, doxorubicin or paclitaxel administered with an experimental cancer vaccine in a mouse model reduced vaccine efficacy, whereas the same doses given prior to vaccination improved vaccine efficacy. 129,131 Immunostimulating interventions often activate immunosuppressive feedback mechanisms, which prevent excessive immune responses. For example, on the one hand TLR agonists induce production of type I IFN and proinflammatory cytokines, such as IL-12, IL-1b, TNF-a and IL-6, but on the other hand these agents induce anti-inflammatory molecules, such as IL-10 and PGE2.…”

Identification and Validation of Targets for Cancer Immunotherapy: From the Bench-to-Bedside

“…These include cellular immunotherapy [119], whole call vaccines [120], multidrug resistance [121] and DCs [122]. Targeted therapeutic strategies along with ever improving designs in clinical trials pave the way for further success [123].…”

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

“…Finally, immunotherapy could represent an important adjuvant to treat MDR, as resistance to immunotherapy generally is unrelated to the classical mechanisms of resistance to cytotoxic agents. Immunotherapy to combat MDR could consist of direct immune attack against MDR positive cells, using MDR as an immune target to deliver cytotoxic drugs, taking advantage of other immune properties of MDR positive cells or application of immunotoxins expressed under MDR control [498,499]. Regarding therapeutic approaches against drug resistance, nanodrug carriers, in particular liposomes, are widely explored [500][501][502].…”