by T cell receptor (TCR) therapy is an emerging treatment approach that harnesses the power of a patient’s own immune cells to fight cancer. Unlike other immunotherapies, such as checkpoint inhibitors, this therapy directly targets specific cancer-causing proteins, or antigens, inside tumor cells. This allows the treatment to be highly targeted while sparing healthy cells.
Workings
TCR therapy works by reprogramming a patient’s T cells, a type of white blood cell critical to the immune system, to recognize and kill cancer cells. In a normal immune response, T cells detect foreign or abnormal peptides displayed on the surface of cells via interactions between a T cell receptor (TCR) and the target peptide-MHC complex.
In TCR therapy, T cells are collected from a patient’s blood and genetically engineered in the laboratory to express an artificial TCR recognizing a cancer-specific antigen. This ‘tumor-specific’ TCR allows the modified T cells to precisely target cells presenting the marker, even if the native T cells cannot. The genetically altered T cells are then infused back into the patient’s bloodstream by intravenous infusion where they can seek out and destroy cancer cells bearing the targeted antigen.
Target Antigens In TCR Therapy
Researchers have identified several tumor-associated antigens that are ideal targets for therapy. Some of the most common targets include:
– NY-ESO-1: Found in many advanced cancers including melanoma, lung, bladder, esophageal, ovarian, and liver cancers. Considered one of the most immunogenic tumor antigens.
– MAGE-A3: Expressed in over 40% of melanomas and various other solid tumors such as lung and bladder cancers.
– HPV16 E7: Associated with human papillomavirus which causes cancers like cervical and head/neck cancers.
– MART-1/Melan-A: Highly specific to melanoma cells and not expressed in other healthy tissues.
– CD19: Expressed on B cell malignancies including various leukemias and lymphomas. Promising early results in acute lymphoblastic leukemia.
Clinical Trials Of TCR Therapy
Several Clinical Trials Have Demonstrated The Potential Of This Therapy In Treating Both Solid And Liquid Tumors:
– Researchers at the National Cancer Institute treated 10 patients with metastatic melanoma using T cells engineered to target the MAGE-A3 antigen. Two patients achieved complete remissions ongoing at 31 and 28 months post-treatment.
– University of Pennsylvania doctors treated 10 multiple myeloma patients with CD19-targeted T cells. After treatment, 3 patients went into complete remission and 4 had partial responses. No relapses reported after 19-27 months.
– A clinical trial led by Adaptimmune reported positive interim results in synovial sarcoma using T cells targeting the NY-ESO-1 antigen. 5 out of 11 evaluable patients achieved responses including one durable complete response ongoing over 24 months.
– Researchers at the National Institutes of Health recently published outcomes in metastatic cervical cancer using T cells engineered to target HPV16 E6&E7 proteins. 2 out of 9 patients had complete responses and 3 others had partial responses or stable disease.
Overcoming Challenges In Therapy
While initial results are promising, wider application of therapy faces some challenges that researchers continue trying to overcome:
– On-target, off-tumor toxicity: TCRs must discriminate tumor cells from normal tissues expressing the same antigen at low levels to avoid potentially life-threatening ‘on-target, off-tumor’ toxicities. Careful antigen selection is key.
– Limited T cell persistence: Adoptively transferred TCR-modified T cells face a hostile tumor microenvironment and may not persist long-term in patients. Efforts focus on improving T cell fitness and self-renewal capacity.
– Imprecise TCRs: Early TCR clones suffered from cross-reactivity with non-targeted proteins containing similar peptides. Advances in screening and cloning have reduced but not eliminated this problem.
– Tumor escape: As with other immunotherapies, cancers can evolve to downregulate targeted antigens and evade therapy over time. Combination regimens aim to prevent or counter this.
Ongoing Advancements And Future Promise
Researchers are continuously working to address the challenges and further improve therapy. Areas of active development and refinement include better TCR cloning techniques, combination therapies, management of on-target toxicities, reengineering T cells for enhanced persistence and tumor killing, and targeting multiple antigens simultaneously.
With its ability to target shared cancer antigens with exquisite precision, therapy has tremendous potential in the treatment of both solid and liquid tumors. As the field matures through ongoing clinical research and technological advancements, therapy is positioning itself at the forefront of personalized immunotherapy for cancer.
*Note:
1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
About Author - Priya Pandey
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