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Expanding CAR T-cell therapy into solid tumours

In CAR T-cell therapy, immune cells, called “T cells,” are genetically engineered to express a synthetic receptor, called a chimeric antigen receptor (CAR). This receptor is designed to bind to a single, specific protein (antigen) found on the surface of the patient’s cancer cells. When the engineered T cells encounter the target antigen, they proliferate and coordinate an immune response to destroy the cells expressing that antigen. 

Approved CAR T-cell therapies have shown remarkable results in patients with certain types of blood cancers. However, further innovations are needed before CAR T-cell therapies can be used to treat solid tumours. Here, we review a range of approaches that researchers are taking to improve the efficacy and safety CAR T-cell therapies in solid tumours. As this research evolves, a synthesis of innovations are poised to bring CAR T-cell therapies targeted against more cancers to a greater number of patients.

Selecting the right target for solid tumours

In the evolution of CAR T-cell therapy, the first major hurdle was engineering a working T-cell receptor that was cancer specific. At present, all approved CAR T-cell therapies target either the proteins CD19 or B-cell maturation antigen, which are antigens associated with cell development that are reliably and highly expressed on blood cancer cells, but have limited expression on healthy cells. Meanwhile, analogous target antigens for solid tumours have proved elusive. Solid tumours have a wide array of potential antigen targets. Many antigens are expressed heterogeneously, and the antigens highly expressed on solid tumours are often also expressed on healthy tissue.

Solid-tumour antigen candidates

While no CAR T-cell therapies targeting solid tumour antigens have yet been approved, a few promising antigen candidates for solid tumours have been identified. One of these antigen targets, CLDN6, is an embryonic gene, which enables cancers to metastasize.1 The antigen is present in most testicular cancers, as well as in some ovarian, non-small cell lung, gastric, breast and endometrial cancers, and is normally silenced at birth. In a 2022 phase 1/2a trial, a CLDN6-directed CAR T-cell therapy, called BNT211-01, displayed one of the first examples of CAR T-cell efficacy and tolerability in solid tumours.2 Additional solid tumour targets that have shown preliminary promise in clinical trials include the protein IL13Ra2, which is being investigated as a CAR T-cell target for glioblastoma, and the prostate stem cell antigen, which is under investigation for prostate cancer.3,4

Upregulating tumour antigen expression

Most solid tumours have heterogeneous antigen expression, meaning that some tumour cells may express an antigen more strongly than others, while some may not express that antigen at all. This heterogeneity is likely one important reason for the diminished initial and durable CAR T-cell response.5 In cases where antigen heterogeneity is a problem, drugs that upregulate tumour antigen expression may increase the durability of CAR T-cell therapies. Some drugs in development for the upregulation of tumour antigen expression include (1) an inhibitor of the enhancer of zeste homolog 2 (EZH2) for the increased expression of a bone cancer antigen (GD2); (2) inhibitors of histone deacetylase; and (3) inhibitors of DNA methyltransferase.6–8

Improving CAR T-cell therapy delivery and proliferation

In the effort to expand CAR T-cell therapies to solid tumours, engineering a well-targeted receptor will be vital, but not sufficient. To attack solid tumours, CAR T cells must first migrate from blood vessels to the tumour tissue. Then, they must penetrate the extracellular matrix and vasculature that surround a solid tumour and help protect it from the immune system. Once inside a tumour, the CAR T cell must overcome an immunosuppressive tumour microenvironment, and coordinate an immune response with the rest of the immune system.9

Meanwhile, CAR T-cell therapy also needs to avoid targeting healthy cells or otherwise overstimulating the patient’s immune system, which can cause severe side effects, including cytokine release syndrome, a toxic and potentially lethal side effect of CAR T-cell therapy resulting from excessive inflammatory cytokines in the circulatory system. A number of approaches intended to improve the efficacy and safety of CAR T-cell therapies for solid tumours are currently in development, including combination therapies; CAR T-cell therapies engineered to express or respond to specific cytokines; and CAR T-cell therapies with built-in suicide genes.

CAR T-cell combination therapy

Combining CAR T-cell therapies for solid tumours with other immunotherapies, such as immune checkpoint inhibitors or vaccines, may help improve their function within an immunosuppressive tumour microenvironment. For example, mRNA vaccines lead to target antigen expression on T-cell-activating immune cells. The resulting CAR T-cell proliferation helps the therapy persist in immunosuppressive conditions and allows the therapy to be administered at lower initial doses.10 In fact, a 2022 phase 1/2a trial of CLDN6-directed CAR T-cell therapy, in combination with an mRNA vaccine, displayed one of the first examples of CAR T-cell efficacy in solid tumours.2 In the study, 43 percent of patients treated with a combination mRNA vaccine and CAR T-cell therapy exhibited tumour shrinkage.

Engineering CAR T cells to express or respond to cytokines

Physical barriers, including the extracellular matrix and the vasculature surrounding a solid tumour, make it difficult for CAR T-cell therapies to penetrate the tumour. Boosting CAR T cells’ expression of some cytokines, or engineering CAR T cells with cytokine receptors, could make solid tumours easier for CAR T cells to infiltrate.11 Cytokines are small proteins that immune cells use to signal each other and orchestrate the immune response. For example, the expression of the cytokine IL-2 has been used to increase CAR T-cell proliferation following administration.12 However, CAR T-cell therapies that boost expression of cytokines also raise the risk of cytokine release syndrome. To avoid the increased risk of toxic side effects, recent research suggests engineering CAR T cells to express cytokines that are tethered to the surface of the cell can help restrict cytokine activity to the area around the T cell. This reduces the risk of cytokine release syndrome, while also making it easier for the CAR T cell to be trafficked to metastasis in other areas of the body. In 2023, researchers saw preclinical success tethering the cytokine IL-12 to a tumour-associated glycoprotein 72-directed CAR T-cell therapy intended to treat ovarian cancer.13

Improving CAR T-cell safety with suicide genes

At present, many patients who receive CAR T-cell therapy experience severe side effects, including cytokine release syndrome, which require close monitoring and management by experienced clinicians in specialised centres. To improve the safety of future CAR T-cell therapies, researchers are working on developing new strategies to control CAR T-cell activity after the therapy has been administered, which is especially important in cases where CAR T-cell therapy is causing severe side effects and should be aborted.

One method is to rapidly terminate a CAR T-cell therapy – in cases of severe side effects – through the activation of a suicide genes, which rapidly induce CAR T-cell death. One commonly used suicide gene system relies on the modified protein Caspase-9, which can trigger the death of a T cell when it is crosslinked by a small molecule with another protein. Rimiducid, one of the small molecules that can trigger the Caspase-9 suicide-gene, has recently been demonstrated as an effective “safety switch” in a phase 1/2a trial of a novel CAR T-cell therapy for advanced neuroblastoma, a solid tumor of the neuroendocrine system common in infants. In the trial, one patient who experienced especially severe side effects received two infusions of rimiducid, which rapidly eliminated the CAR T-cell therapy and resolved life-threatening toxicities.14 Additional methods in development to control CAR T-cell therapies post-administration include modular CAR T-cell therapies and CAR T-cell therapies engineered with expression switches.15

History repeats

Many of the challenges facing CAR T-cell therapy for solid tumours remain unresolved. However, if history is a guide, these obstacles are not insurmountable. Blood cancers are often selected for the development of novel therapies because tumour cells circulating in the blood are easier to access than tumour cells in tissue, and treatments are easier to deliver. Treatment options, such as chemotherapy and stem-cell transplant, were first developed for blood-based cancers, and then modified for the treatment of solid tumours. A number of recent advancements – including the identification of solid tumour-specific antigens, the development of combination therapies, and the development of suicide genes – are bringing this targeted immunotherapy for solid tumours closer to reality.

Learn more about innovations in CAR T-cell therapy in our whitepaper, ‘Approaching the CAR T-cell therapy horizon’.

References:

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  2. Mackensen A. BNT211-01: A phase I trial to evaluate safety and efficacy of CLDN6 CAR T cells and CLDN6-encoding mRNA vaccine-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumours. In: ; 2022.
  3. Oct 1 - Session 3 - Immunotherapy: Hype and Hope.; 2021. Accessed January 25, 2023. https://soc-neuro-onc.vids.io/videos/a79dd8bb1618e6c72e/b_fri-oct-1-session-2-first-annual-conference-on-cns-clinical-trials
  4. Mustang Bio Announces Initial Phase 1 Data on MB-105 for Patients with PSCA-positive Castration Resistant Prostate Cancer. Published online October 26, 2020. Accessed January 25, 2023. https://ir.mustangbio.com/news-events/press-releases/detail/36/mustang-bio-announces-initial-phase-1-data-on-mb-105-for
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  7. Bae J, Hideshima T, Tai YT, et al. Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors. Leukemia. 2018;32(9):1932-1947. doi:10.1038/s41375-018-0062-8
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  10. Huff AL, Jaffee EM, Zaidi N. Messenger RNA vaccines for cancer immunotherapy: progress promotes promise. J Clin Invest. 132(6):e156211. doi:10.1172/JCI156211
  11. Mollica Poeta V, Massara M, Capucetti A, Bonecchi R. Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy. Front Immunol. 2019;10. Accessed January 25, 2023. https://www.frontiersin.org/articles/10.3389/fimmu.2019.00379
  12. Li HS, Israni DV, Gagnon KA, et al. Multidimensional control of therapeutic human cell function with synthetic gene circuits. Science. 2022;378(6625):1227-1234. doi:10.1126/science.ade0156
  13. Lee EHJ, Murad JP, Christian L, et al. Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. Nat Commun. 2023;14(1):4737. doi:10.1038/s41467-023-40115-1
  14. Del Bufalo F, De Angelis B, Caruana I, et al. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. N Engl J Med. 2023;388(14):1284-1295. doi:10.1056/NEJMoa2210859
  15. Celichowski P, Turi M, Charvátová S, et al. Tuning CARs: recent advances in modulating chimeric antigen receptor (CAR) T cell activity for improved safety, efficacy, and flexibility. J Transl Med. 2023;21(1):197. doi:10.1186/s12967-023-04041-6
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