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Targeting the immune-suppressive tumor microenvironment to potentiate CAR T cell therapy

Tiffany C. Y. Tang

Children’s Cancer Institute, University of New South Wales, Sydney, Australia

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Ning Xu

Children’s Cancer Institute, University of New South Wales, Sydney, Australia

Kids Cancer Center, Sydney Children’s Hospital, Sydney, Australia

Alla Dolnikov

Children’s Cancer Institute, University of New South Wales, Sydney, Australia

Kids Cancer Center, Sydney Children’s Hospital, Sydney, Australia

DOI: 10.15761/CRR.1000203

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Abstract

Chimeric antigen receptor (CAR) T cell therapy is a promising new immunotherapy that reprograms patient T lymphocytes to specifically recognize and kill tumor cells. CAR T cell therapy has produced some dramatic responses in acute lymphoblastic leukemia and lymphomas, but responses have been less spectacular in solid tumors. To make CAR T cell therapy effective for solid tumors, CAR T cells must overcome an immune-suppressive tumor microenvironment (TME) that attenuates CAR T cell function. This review provides insights into mechanisms of CAR T cell therapy resistance with respect to the TME and offers strategies for improving CAR T cell therapy by targeting immune-suppressive factors in tumors.

Key words

cancer, CAR T cells, tumor microenvironment

Chimeric antigen receptor (CAR) T cell therapy

CAR T cell therapy is a promising new immunotherapy that provides potential curative treatments for cancer. CARs consist of a tumor-targeting monoclonal antibody-derived single chain variable fragment (scFv) fused to a T cell receptor-derived cytoplasmic signaling domain CD3ζ and one or more domains derived from co-stimulatory T cell receptors CD28, 4-1BB, or OX40 (Figure 1A) [1]. When expressed by T cells, CARs redirect T cell specificity to antigens expressed on cancer cells. To deliver CAR T cell therapy, patient T cells are genetically modified to express CAR and then amplified ex vivo to numbers suitable for adoptive cell therapy [2]. Recent clinical data provided strong evidence that T cells from patients with B cell malignancies can successfully be redirected to initiate an effective anti-tumor response even at advanced stages of the disease [3-15]. In relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) and certain types of lymphoma, this strategy has led to dramatic complete responses in more than 80% of patients treated with CD19-targeting (CAR19) T cell therapies [3-15]. The FDA has recently approved the CAR T cell products axicabtagene ciloleucel and tisagenlecleucel to treat relapsed or refractory B-ALL and diffuse large B cell lymphoma (DLBCL) [8,12,16,17]. CAR T cells can thus be considered as “designer drugs” that are personalized to patients’ needs and manufactured to clinical standards.

Figure 1A. Chimeric antigen receptor (CAR) T cells. Derived from tumor-specific monoclonal antibodies, the extracellular single chain variable fragment (scFv) recognizes tumor-associated antigens (TAA) and is connected via the hinge to the transmembrane domain (TM) that anchors to the CAR T cell’s plasma membrane. Attached to the TM are intracellular co-stimulatory (CD28, 4-1BB, or OX40) and T cell receptor CD3ζ-derived signaling domains that activate the CAR T cell

Figure 1B. Immune-suppressive cells in the TME lower CAR T anti-tumor activity. Regulatory T cells (Tregs) inhibit CAR T cell proliferation and cytokine production via TIM-3 and prostaglandin E2 (PGE2). Myeloid-derived suppressor cells (MDSCs) suppress T cell activation via cystine (Cys-Cys) and cysteine (Cys) deprivation [72], and facilitate Tregs recruitment and expansion via IL-10 and TGF-β [73]. Type II tumor-associated macrophages (TAMs) release PGE2 and TGF-β, and express CD80/CD86 that preferentially binds to the inhibitory CTLA-4 receptor in CAR T cells. Cancer-associated fibroblasts (CAFs) physically prevent CAR T cells from accessing tumor antigens. Tumor cells express MHC class II, galectin-9 (Gal9), and PD-L1 that bind to the LAG3, TIM-3, and PD-1 receptors on CAR T cells to promote CAR T cell exhaustion and apoptosis [71]. Immune-suppressive metabolites kynurenine and adenosine are produced via indolamine-2,3-dioxygenase (IDO) and CD39/CD73, and IDO is involved in activation of Tregs [74]

Using viral vectors to transfer CAR genes to T cells requires complex protocols that are time-consuming and expensive. Compared to viral vectors, non-viral transposon-based gene delivery systems offer a simpler and cheaper alternative for CAR T manufacture with no infectious potential [18-20]. Novel CAR T cells generated using Sleeping Beauty (SB) and PiggyBac (PB) transposon/transposase systems have demonstrated strong efficacy against leukemia cells in preclinical mouse models [18-21]. This preclinical data provided the basis for testing transposon-based CAR T cells in clinical trials in USA, Australia and China [21-23]. Importantly, the decreased cost and complexity of non-viral genome modification methods can widen patient access to CAR T cell therapies by increasing the number of hospitals capable of implementing them.

Mechanisms and strategies to overcome immune suppression in the tumor microenvironment (TME)

Recent clinical studies have shown that CAR T cells can cure select patients with cancer, while others experience transient or no clinical benefit [4,5,10,15,24,25]. Short duration of remission in patients treated with CAR T cells can be associated with functional CAR T cell exhaustion in the immune-suppressive TME [6,7,26,27]. The immune-suppressive TME considerably reduces the efficacy of CAR T cell therapy against solid tumors such as prostate [28-30], ovarian [31-35], breast [36-39], pancreatic [40-44], and brain [45] cancers. Disialoganglioside (GD2)-targeting CARs incorporating CD28 and OX40 co-stimulatory domains showed efficient CAR T cell infiltration of neuroblastoma tumors; however, the suppression of tumor growth was marginal, suggesting that CAR T cell function is compromised by the immune-suppressive TME [46,47].

The immune-suppressive TME is enriched with regulatory immune cells such as regulatory T cells (Tregs) [48-55], myeloid-derived suppressor cells (MDSCs) [36,39,56,57], tumor-associated macrophages (TAMs) [58-60], and cancer-associated fibroblasts (CAFs) [35,61]. These regulatory immune cells inhibit CAR T cells by releasing suppressive factors such as TGF-β [28,30,58,62], IL-4 [43,63,64], IL-10 [40], prostaglandin E2 (PGE2) [65], and immune-suppressive metabolites such as kynurenine and adenosine via indolamine-2,3-dioxygenase (IDO) [59,66,67] and CD39/CD73 respectively [38,68-70]. Additionally, tumor cells often down-regulate T cell co-stimulatory ligands that would normally promote CAR T cell function, while up-regulating immune-suppressive ligands (MHC class II, galectin-9, PD-L1 and CD86) that activate immune checkpoints (LAG3, TIM-3, PD-1 and CTLA-4) in adoptively transferred CAR T cells (Figure 1B) [71]. Chemoresistant and chemorefractory pediatric B-ALLs exhibit significant interpatient heterogeneity in the expression of 35 genes that encode T cell co-stimulatory and inhibitory ligands, and in vitro models showed association of CD86, CD70, ICOSL, OX40, and IL-10 with CAR T cell expansion and exhaustion [26]. B-ALLs exhibit low expression of PD-L1 and CD80/CD86, which activates the PD-1 and CTLA-4 checkpoints in CAR T cells [26]. Unlike B-ALLs, T cell acute lymphoblastic leukemia (T-ALL) cells express high levels of PD-L1 and often CD80/CD86, and so can be considered as more immune-suppressive than B-ALL in this respect [26]. B-ALLs from some patients, however, express MHC class II and galectin-9 (Gal9) that bind to the LAG3 and TIM-3 receptors on CAR T cells to promote CAR T cell exhaustion and apoptosis [71].

CARs with multiple co-stimulatory domains and/or genome-edited checkpoint receptors have been engineered to mitigate the immune-suppressive TME [70,75-83]. New approaches also combine CAR T cell therapy with chemotherapeutic drugs, epigenetic modulators, or targeted drugs that attenuate immune suppression in the TME in addition to direct anti-tumor activity [32,36,45,47,48,50,67,84-89]. Some epigenetic drugs up-regulate the tumor’s antigen expression for targeting by CAR T cells, up-regulate T cell co-stimulatory ligands, or induce type I interferon responses in tumors against pro-viruses integrated into target cell genomes [90]. The hypomethylating agent 5-azacitidine (AZA) sensitizes leukemia and lymphoma cells to CAR T cell therapy by modulating the TME in leukemia and inducing OX40L to promote CAR T cell function [20,86]. Other epigenetic modulators down-regulate the immune-suppressive ligands that activate specific immune checkpoints in CAR T cells. JQ1, a potent small-molecule bromodomain and extra terminal domain (BET) inhibitor: down-regulates PD-L1 expression in neuroblastoma and sensitizes neuroblastoma cells to CAR T cell therapy [47,85]. JQ1 also promotes CAR T cell activity by up-regulating interferon regulatory factor 7 (IRF7) signalling to activate type I interferon responses [47,85].

Combining CAR T cells with specific targeted drugs have been shown to promote CAR T cell function [67,84,87,89]. Ibrutinib is a small-molecule drug that binds permanently to Bruton’s tyrosine kinase and is used to treat chronic lymphocytic leukemia (CLL). CLL patients showed prolonged remission after combined treatment with ibrutinib and CAR19 T cells [84,87,89]. Ibrutinib induced mobilization of the disease into blood or bone marrow, where it is highly responsive to CAR T therapy [84,87,89]. Lenalidomide, another targeted drug for treating multiple myeloma (MM), delayed the onset of CAR T cell functional exhaustion in the immune-suppressive TME by potentiating CAR T cells that target B cell maturation antigens in MM [67].

Another promising strategy involves using checkpoint inhibitors to rejuvenate exhausted CAR T cells [70,75-83]. Up-regulation of specific checkpoint ligands such as PD-L1 in inflamed TME induces premature CAR T cell exhaustion. PD-1 checkpoint blockade with PD-1 and/or PD-L1 antagonistic antibodies [91-94] acts to rescue CAR T cells from exhaustion and improve their cytolytic activity in melanoma [77,95-97]. PD-1 checkpoint inhibitors induced remission in B-ALL patients that relapsed following CAR T cell therapy [98], but did not promote CAR T cell efficacy in recent neuroblastoma clinical studies [99], suggesting that additional factors in the TME may be involved in CAR T cell exhaustion in neuroblastoma patients.

Agents targeting Tregs, MDSCs, TAMs, and CAFs in the TME are currently being investigated in the context of CAR T cell therapy against hematological and solid tumors [100-107]. Macrophage colony stimulating factor 1 (CSF1) and granulocyte macrophage colony stimulating factor (GM-CSF) antagonists were shown to inhibit TAMs and MDSCs and promote CAR T cell function [100-102].

Concluding remarks

CAR T cell therapy has been a major breakthrough in cancer treatment. Despite encouraging clinical results in certain hematological malignancies, high resistance to CAR T cell therapies has often been reported in patients with solid tumors. Multiple mechanisms contributing to CAR T resistance have led to the design of complex therapeutic strategies to avoid immune suppression in the TME of solid tumors and to increase tumor cell susceptibility to CAR T cell attack. Resistance mechanisms need to be examined in different contexts in order to design effective therapeutic combinations and improve the efficacy of CAR T cell therapy.

Acknowledgments

This work was funded by Kids Cancer Project grants. The authors thank Dr Kenneth Micklethwaite from Westmead Institute of Medical Research, Sydney, for providing constructive discussion of the manuscript.

Author contributions

All authors participated in the preparation, writing and revision of the manuscript. All authors have read and agreed to the published version of the manuscript.

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Editorial Information

Editor-in-Chief

Dung-Fang Lee
The University of Texas

Article Type

Review Article

Publication History

Received: March 16, 2020
Accepted: March 26, 2020
Published: March 31, 2020

Copyright

©2020 Tiffany C. Y. Tang. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Tiffany C. Y. Tang, Ning Xu and Alla Dolnikov (2020) Targeting the immune-suppressive tumor microenvironment to potentiate CAR T cell therapy. Cancer Rep Rev 4: DOI: 10.15761/CRR.1000203

Corresponding author

Alla Dolnikov

Children’s Cancer Institute, University of New South Wales, Sydney, Australia

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Figure 1A. Chimeric antigen receptor (CAR) T cells. Derived from tumor-specific monoclonal antibodies, the extracellular single chain variable fragment (scFv) recognizes tumor-associated antigens (TAA) and is connected via the hinge to the transmembrane domain (TM) that anchors to the CAR T cell’s plasma membrane. Attached to the TM are intracellular co-stimulatory (CD28, 4-1BB, or OX40) and T cell receptor CD3ζ-derived signaling domains that activate the CAR T cell

Figure 1B. Immune-suppressive cells in the TME lower CAR T anti-tumor activity. Regulatory T cells (Tregs) inhibit CAR T cell proliferation and cytokine production via TIM-3 and prostaglandin E2 (PGE2). Myeloid-derived suppressor cells (MDSCs) suppress T cell activation via cystine (Cys-Cys) and cysteine (Cys) deprivation [72], and facilitate Tregs recruitment and expansion via IL-10 and TGF-β [73]. Type II tumor-associated macrophages (TAMs) release PGE2 and TGF-β, and express CD80/CD86 that preferentially binds to the inhibitory CTLA-4 receptor in CAR T cells. Cancer-associated fibroblasts (CAFs) physically prevent CAR T cells from accessing tumor antigens. Tumor cells express MHC class II, galectin-9 (Gal9), and PD-L1 that bind to the LAG3, TIM-3, and PD-1 receptors on CAR T cells to promote CAR T cell exhaustion and apoptosis [71]. Immune-suppressive metabolites kynurenine and adenosine are produced via indolamine-2,3-dioxygenase (IDO) and CD39/CD73, and IDO is involved in activation of Tregs [74]