Enhancing the efficacy of adoptive cellular therapy by targeting tumor-induced immunosuppression

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From: Immunotherapy(Vol. 7, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 11,972 words
Lexile Measure: 2110L

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Author(s): Paul A Beavis [*] aff1 aff2 , Clare Y Slaney aff1 aff2 , Michael H Kershaw aff1 aff2 aff3 aff4 , Paul J Neeson aff1 aff2 , Phillip K Darcy [*] aff1 aff2 aff3 aff4

Keywords:

adoptive cellular therapy; checkpoint blockade; chemotherapy; chimeric antigen receptor; cytokine; genetic modification; immunosuppression; radiotherapy; T cells; tumor

Background

Recent clinical successes with adoptively transferred lymphocytes (adoptive cellular therapy [ACT]) and agents designed to harness the antitumor potential of the immune system, such as anti-CTLA-4 mAbs (e.g., ipilimumab) and anti-PD-1 mAbs (e.g., nivolumab), represent a major advance in the treatment of certain cancers. Expansion of tumor-infiltrating lymphocytes (TILs) and reinfusion back to the patient remains one of the most potent therapeutic approaches with objective response rates of up to 50% reported [ 1 ]. However, the efficacy of adoptively transferred T cells is curtailed by the immunosuppressive environment engineered by tumors in order to evade the immune system. Preclinical studies have shown that combining adoptive transfer of T cells along with strategies designed to subvert this immunosuppressive environment can enhance the efficacy of ACT. This review discusses some of the more promising approaches and how these approaches can be translated into greater therapeutic benefit in the clinic.

Current challenges to the success of ACT

Although adoptive transfer of expanded TILs has been shown to be highly successful in melanoma, this approach is not readily applicable to other cancer types. TILs can be isolated from other solid tumor types, however, they are often of low frequency and it can be technically challenging to generate sufficient TILs for clinical intervention. Moreover, since it has been reported that a longer telomere length (and therefore enhanced proliferative potential) of adoptively transferred T cells correlates with greater antitumor efficacy [2 ], the prolonged culture periods required to expand a low-frequency TIL are detrimental to the effectiveness of the T cells being transferred back to the patient. An alternative strategy is to genetically engineer T cells to recognize tumor antigens by transducing the T cells with TCR-[alpha][beta] transgenes. Although this strategy has been shown to produce T cells with antitumor activity and positive clinical outcomes in a subset of patients [ 3 ], these T cells still require the presentation of tumor antigens in the context of MHC, which may be expressed at low levels in some less immunogenic tumor types. One way to bypass this issue is to genetically engineer patients' T cells to express a chimeric antigen receptor (CAR) to directly recognize tumor antigens independently of MHC restriction.

CARs as tools for adoptive cellular immunotherapy

Much effort has been directed at optimizing CAR T-cell function, particularly with regard to the type and number of signaling domains. First-generation CARs comprised an extracellular scFv region fused to the intracellular signaling domain of CD3ζ or Fc[gamma]R [4 ]. Subsequently, second- and third-generation CARs have been developed which incorporate additional costimulatory signaling domains such as CD28 and CD28/4-1BB, respectively [5-8 ]. These additional signaling domains were incorporated to help maintain T-cell function within the immunosuppressive tumor environment and...

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Gale Document Number: GALE|A417580380