TCR T cells ‘poised to play a central role’ in cancer immunotherapy
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The world of cancer cell therapy continues to evolve, and the next breakthrough may include T cells genetically modified to include T-cell receptors that recognize a wider array of tumor-associated antigens.
Development of T-cell receptor (TCR) T-cell therapy has been influenced by the foundational successes of chimeric antigen receptor T-cell therapies for hematologic malignancies and tumor-infiltrating lymphocytes (TILs) for melanoma.
TCR T-cell therapy may become the next tool in the immunotherapy armamentarium, providing a new option to treat solid tumors.
One of the laboratories at the forefront of this effort is led by Marie Bleakley, MD, PhD, MMSC, associate professor, director of cellular therapy and transplantation for pediatric leukemia and Gerdin Family Endowed Chair for Leukemia Research at Fred Hutchinson Cancer Research Center.
Early results with this investigational cell therapy are encouraging, and Bleakley anticipates an expanding role for TCR T-cell therapy over the next decade.
In this installment of In Practice, Bleakley provides an overview on this burgeoning area of cancer cell therapy and discusses which patients may be eligible for ongoing clinical trials.
Healio: Can you describe the emergence of T-cell receptor T-cell therapy?
Bleakley: In a naturally occurring immune response against cancer, T cells recognize tumor-associated antigens and initiate a cancer-killing fight. However, the T cells’ response often is ineffective — especially against advanced malignancies — due to any of several mechanisms, including the recruitment of suppressor cells and the induction of a hostile tumor microenvironment that works against T-cell activity.
Naturally occurring T-cell responses can be enhanced, to a degree, by isolating TILs from tumor tissue, activating and expanding the T cells in the lab, and reinfusing the TIL product into the patient. This has produced clinical responses in some patients, but the technology is limited primarily to solid tumors with surgically accessible lesions.
Marrow-infiltrating lymphocytes (MILs) are being investigated for treatment of hematologic malignancies, but neither TILs nor MILs can be generated for all patients. These approaches are not highly tumor antigen-specific, and only a subset of the T cells react to tumors. These approaches provide more T cells, but not necessarily better or more targeted T cells.
Adoptive immunotherapy with engineered T cells is at the forefront of cancer research and treatment, as scientists and clinicians seek ways to improve tumor targeting, overcome the limitations of naturally occurring T-cell responses and outmaneuver barriers. T-cell receptor transgenic T cells (TCR-Ts) are the latest advancement in this field and are poised to play a central role in cellular cancer immunotherapies.
Healio: Can you compare TCR-T with CAR-T?
Bleakley: Both CAR-T and TCR-T are adoptive cellular therapies that have a defined, preselected target with high expression on certain tumors but low or absent expression on normal tissue.
CARs are artificial antigen-specific receptors that can be transferred into T cells to produce an engineered T cell — a CAR T cell — with defined specificity for a cell surface molecule, such as the CD19-targeted CAR T-cell treatments available for some blood cancers.
TCR-T also involves engineering cells, but it has a significant advantage over CAR T-cell therapy. TCR-T can target peptides derived not just from cell surface proteins but also from intracellular proteins. This is important because not all malignancies have a suitable surface target. TCR-T can allow access to the intracellular malignant proteome.
Healio: What are the advantages and disadvantages of each approach?
Bleakley: Unlike TCR-T cells, CAR T cells are MHC/HLA-independent, so they can be used in patients of all HLA types. Despite CARs being expressed at higher surface levels than TCRs, CARs have less efficient signaling kinetics, leading to lower sensitivity to antigens. Also, without careful monitoring and management of the release of some cytokines, such as interleukin (IL)-2 and IL-6, CAR T-cell therapy can lead to toxic cytokine release syndrome (CRS).
Transgenic TCRs, on the other hand, harness an endogenous T-cell response that has been fine-tuned by the evolution of the immune system, and they are rarely associated with clinically significant CRS. There is also the previously mentioned advantage that TCR-T can target peptides derived not just from cell surface proteins, but also from intracellular proteins.
Healio: Is TCR-T available only via clinical trials? Which patients might be treated with this therapy?
Bleakley: TCR-T cell therapies are only available on clinical trials. Patients with a variety of cancers might be eligible for these trials, including patients who have tried multiple other types of therapy. Clinicians and patients should check clinicaltrials.gov using the search term TCR to see what may be available in their area.
Healio: For which malignancies is TCR-T being evaluated?
Bleakley: TCR T-cell therapies are being evaluated for leukemias, melanoma, sarcoma, oropharyngeal and nasopharyngeal cancer, other head and neck cancers, Merkel cell carcinoma, cervical cancer, hepatocellular carcinoma, lung cancer, pancreatic cancer, and others.
Healio: Does TCR-T hold promise for the treatment of solid tumors?
Bleakley: Yes, certainly. In fact, the first clinical trials of TCR T-cell therapy were performed for melanoma by investigators at the NCI. Some patients from these early trials have experienced complete and durable responses.
Healio: What has clinical research indicated about the safety and effectiveness of TCR-T?
Bleakley: TCR T-cell therapy generally has been found to be safe, with less frequent complications involving CRS or neurotoxicity than CAR T-cell therapy. There have, however, been a few serious safety issues with TCR T-cell products. These products are no longer being used to treat patients. TCR T-cell therapy also has been effective for some individuals with a variety of cancers.
Healio: Are you or Fred Hutch conducting research in this area?
Bleakley: Fred Hutchinson Cancer Research Center has several TCR T-cell immunotherapy trials open to accrual. They include the following:
- NCT04639245: Genetically engineered cells (MAGE-A1-specific T-cell receptor-transduced autologous T cells) and atezolizumab (Tecentriq, Genentech) for the treatment of metastatic triple-negative breast cancer, urothelial cancer or non-small cell lung cancer;
- NCT04809766: Mesothelin-specific T cells (FH-TCR-Ts) for the treatment of metastatic pancreatic ductal adenocarcinoma;
- NCT03747484: Gene-modified immune cells (FH-MCVA2TCR) for treatment of patients with metastatic or unresectable Merkel cell cancer; and
- NCT03326921: HA-1 T TCR T-cell immunotherapy for the treatment of patients with relapsed or refractory acute leukemia after donor stem cell transplant.
Healio: What type of infrastructure would be required to deliver TCR-T to patients?
Bleakley: Cancer centers that deliver CAR T-cell therapies to patients also would be in a good position to administer TCR T-cell therapies.
Healio: Is there anything else clinicians should know about TCR-T?
Bleakley: TCT T-cell therapy is a promising and growing area of immunotherapy. Various technical challenges have been overcome and we can expect the promise of TCR T-cell therapy to be fully realized in the next 5 to 10 years.
For more information:
Marie Bleakley, MD, PhD, MMSC, can be reached at mbleakle@fredhutch.org.
Reference:
Morgan RA, et al. Science. 2006;doi:10.1126/science.1129003.
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