Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities

ABSTRACT

Introduction: Cancer therapy has been transformed by the demonstration that tumor-specific T-cells can eliminate tumor cells in a clinical setting with minimal long-term toxicity. However, significant success in the treatment of leukemia and lymphoma with T-cells using native receptors or redirected with chimeric antigen receptors (CARs) has not been recapitulated in the treatment of solid tumors. This lack of success is likely related to the paucity of costimulatory and cytokine signaling available in solid tumors, in addition to a range of inhibitory mechanisms.

Areas covered: We summarize the latest developments in engineered T-cell immunotherapy, describe the limitations of these approaches in treating solid tumors, and finally highlight several strategies that may be useful in mediating solid tumor responses in the future, while also ensuring safety of engineered cells.

Expert opinion: CAR-T therapies require further engineering to achieve their potential against solid tumors. Facilitating cytokine signaling in CAR T-cells appears to be essential in achieving better responses. However, the engineering of T-cells with potentially unchecked proliferation and potency raises the question of whether the simultaneous combination of enhancements will prove safe, necessitating continued advancements in regulating CAR-T activity at the tumor site and methods to safely switch off these engineered cells.

KEYWORDS:

• Cancer
• chimeric antigen receptor (CAR)
• cytokine
• immunotherapy
• synthetic biology
• T cell

Article highlights

• The initial success of CAR T-cells against B-cell malignancies was driven by unique contexts of antigen expression, costimulation, and microenvironment that are not operable in solid tumors.

• CAR T-cell efficacy against solid tumors has in particular been hampered by lack of signal 3 activation via cytokine stimulation, a deficiency not addressed in most CAR T-cell schemes today.

• Engineered cytokine signaling systems such as constitutively active cytokine receptors, chimeric cytokine receptors, and tethered cytokines have shown potential to endow engineered T-cells with potent persistence and antitumor properties.

• Genetic modifications to improve T-cell infiltration into solid tumors, circumvent extracellular matrix barriers, and provide resistance to immunosuppressive molecules will enhance the efficacy of adoptive immunotherapy strategies.

• Synthetic biology has led to the development of new methods to regulate apoptosis of modified T-cells as potential safety switches, while also providing methods of regulating CAR-T activation with small molecules.

• Split antigen recognition approaches are an exciting modality to bring specificity to CAR T-cell therapies and avoid responses in unwanted tissues.

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Declaration of interest

T Shum has filed patents related to adoptive T-cell therapy . RL Kruse has filed a patent on CAR T-cell technology. C. Rooney is on the scientific advisory boards of Cell Medica and CellGenix and has a research agreement with Tessa Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was funded by a Reach Award from Alex’s Lemonade Stand Foundation, SCOR grant from the Leukemia & Lymphoma Society (R7016), and grants from the National Institute of Health/National Institute of Cancer (NIH-NCI P50 CA126752, NIH-NCI. PO1 CA94237). T Shum was also supported by grants from the National Institute of Health (NIH-T32DK060445 and NIH-HL092332).