The cancer immunotherapy landscape has recently observed a considerable breakthrough with the US Food and Drug Administration (FDA)’s recent approval of Tecelra® (Afamitrisgene autoleucel Afami-cel), established by Adaptimmune Therapeutics. This approval signifies the first T-cell receptor (TCR) therapy for solid tumors specifically targeting unresectable or metastatic synovial sarcoma in adults. Tecelra’s success offers patients with limited treatment options a reason for renewed optimism. It paves the way for wider applications in solid tumor therapy, an area of progress that has been met with significant challenges.
Mechanism of action and comparison with CAR-T
Tecelra is a novel class of engineered autologous T-cell therapies that target the cancer germline antigen MAGE-A4, which is expressed in several tumors but missing in healthy tissues.
Unlike chimeric antigen receptor (CAR) T-cell therapies, which can identify surface antigens, TCR-T cell therapies like Tecelra can recognize intracellular antigens presented by primary histocompatibility complex (MHC) molecules. This basic difference extends the range of possible targets and opens up new doors for addressing solid tumors.
While a key difference between CAR-T and TCR-T therapies is in their target recognition, it also lies in their MHC dependence and antigen scope. Whereas CAR-T cells have been developed to identify specific surface proteins, TCR-T cells can target a more extensive range of antigens, such as those within the cell. However, this benefit is increasingly complex, as patients who can receive TCR-T therapies must possess specific HLA antigens with tumors expressing the target antigen, which, here, is MAGE-A4.
Clinical efficacy and safety profile
The FDA granted approval for Tecelra based on results from a Phase 2 trial involving 44 synovial sarcoma patients. The study revealed an overall response rate of 43 %, with 17 % of patients sustaining their response for a minimum of 12 months. The average duration of response was 36 weeks, spanning from 9.1 to 164.9 weeks, and the average progression-free survival was 21.1 weeks.
These outcomes are crucial given the limitations surrounding treatment options and poor prognosis related to synovial sarcoma, a rare soft tissue cancer that approximately 1,000 people suffer from each year in the U.S.
While the efficacy data demonstrates potential, it’s key to consider Tecelra’s safety profile. Common side effects such as cytokine release syndrome (CRS), fatigue, pyrexia, and decreased lymphocyte count have been observed. Adverse events were present in 39 % of patients, with CRS being the most common at 20 %. The FDA approval includes a boxed warning for neurotoxicity, hematologic toxicity, and CRS, highlighting the need for meticulous patient observation and control of potential side effects.
Implications for solid tumor immunotherapy
Tecelra’s success and potential in synovial sarcoma paves the way for applying TCR-T therapies to other solid tumors. The capability to target intracellular antigens, in combination with the possibility for deeper tumor penetration and enhanced persistence within solid tumors, makes TCR-T therapy a promising method for cancers that have managed to dodge effective immunotherapy for some time.
Continuous research opens investigations into additional tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs) to extend the potential scope of TCR-T therapies across various cancer types.
For example, the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) antigen has demonstrated promise in clinical trials for synovial sarcoma and melanoma, underscoring the potential scale of TCR-T applications.
Manufacturing challenges and future directions
The production of TCR-T therapies like Tecelra necessitates complex, patient-specific manufacturing processes that present unusual challenges. Each batch must be tailored to individual patients, requiring precision coordination and timing.
Ensuring uniform potency and purity across batches while ensuring production scales meet demand presents major logistical and quality control challenges. These factors are part of the reason why production costs associated with personalized cell therapies remain high, a hurdle that must be overcome for wider adoption and accessibility.
The field of TCR-T therapy continues to progress quickly despite these challenges.
Expanding TCR-T targets
Exploring and validating new, potential targets is a key area of future development in TCR-T therapy. These targets can be classified into two broader groups: TAAs and TSAs.
Figure 1. Trends in the number of TCR-T clinical trials and popular targets. Image Credit: ACROBiosystems
TAAs: TAAs are overexpressed in tumor tissues but show reduced expression in normal tissues. They can stem from germline tissues (cancer germline antigens) or tumor-derived tissues (tissue differentiation antigens). While TAAs are considered good therapeutic targets in TCR-T research, their expression in regular tissues presents a risk of on-target/off-tumor toxicity, requiring careful selection and validation.
Tissue Differentiation Antigens (TDAs): TDAs represent melanoma antigens like MART-1, glycoprotein 100 (gp100), and carcinoembryonic antigens. Currently, several TCR-T therapies targeting these antigens are in clinical trials. A remarkable success in this category is Tebentafusp, a soluble affinity-enhanced TCR-targeting gp100 combined with an anti-CD3 single-chain variable fragment.
Tebentafusp has received approval to treat HLA-A*02:01-positive patients with metastatic uveal melanoma with a Phase 3 randomized trial, which presented a significant overall survival benefit.
Cancer Germline Antigens (CGAs): Most clinical trials targeting CGAs concentrate on members of the MAGE-A protein family and NY-ESO-1. TCR-T cells that target NY-ESO-1 have demonstrated promising results in clinical trials, particularly for treating melanoma and synovial sarcoma.
Across five trials that involved 107 patients, the average overall response rate was around 47 % (ranging from 20 % to 67 %), with eight complete responses and 40 partial responses reported, all without any major side effects.
TSAs: TSAs, otherwise known as neoantigens, are unique to tumor cells and affiliated with tumorigenesis, either through mutations or viral induction. Targeting these neoantigens presents a reduced toxicity risk due to their absence in normal tissues, making them promising targets for future TCR-T therapies.
Mutation-associated neoantigens: These neoantigens derive from non-synonymous mutations associated with oncogenic genetic instability. Public neoantigens are of significant interest, and these typically derive from common mutated driver genes, including TP53, KRAS, or PIK3CA, which can be found in patients presenting a specific HLA allele.
There are multiple clinical trials evaluating TCR-T therapies targeting these public neoantigens, including TCR-T cells targeting KRAS-G12D in pancreatic cancer and KRAS-G12V in other cancers.
Viral antigens: Some cancers are triggered by viral infections, such as human papillomavirus (HPV), hepatitis B virus, Merkel cell polyomavirus, and Epstein-Barr virus. These virally induced cancers demonstrate a unique opportunity for TCR-T therapy.
A clinical trial using HPV16-E6-specific TCR-T cells demonstrated no major toxicity in 17 % of patients (two out of 12), further marking the potential of targeting viral antigens in cancer treatment.
Figure 2. Types of Target Antigens in TCR-T Cell Therapy. Image Credit: ACROBiosystems
Conclusion
The approval of Tecelra marks a major breakthrough in cancer immunotherapy. It offers renewed hope for patients with synovial sarcoma and possibly opens doors for treating a broad spectrum of solid tumors. This development highlights the transformative potential of TCR-T cell therapies in oncology.
As research continues, further refinements in target identification, engineering strategies, and combination approaches are on the horizon. While certain challenges remain in manufacturing, scalability, and managing side effects, Tecelra’s success can expedite innovation in the field.
Continuously developing TCR-T therapies hold great promise for improving outcomes across a range of cancers previously deemed intractable, potentially transforming solid tumor treatment in the coming years.
To support research associated with TCR-T therapies, ACRO Biosystems offers an extensive range of TCR-related antigen MHC-antigen peptide complexes, such as cancer-testis antigens, tissue differentiation antigens, mutation-associated neoantigens, and viral antigens.
These complexes are readily available in monomer, tetramer, and fluorescent-labeled forms, as well as several different HLA subtype backbones. They incorporate native conformations, exceptional stability, and high bioactivity verified through flow cytometry, and they bind particularly well with corresponding TCRs with high affinity, fully aiding your TCR-T drug research process.
References
- Shafer P, Kelly LM, Hoyos V. Cancer Therapy With TCR-Engineered T Cells: Current Strategies, Challenges, and Prospects. Front Immunol. 2022;13:835762. Published 2022 Mar 3. doi:10.3389/fimmu.2022.835762
- Baulu E, Gardet C, Chuvin N, Depil S. TCR-engineered T cell therapy in solid tumors: State of the art and perspectives. Sci Adv. 2023;9(7):eadf3700. doi:10.1126/sciadv.adf3700
- Tsimberidou AM, Van Morris K, Vo HH, et al. T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors. J Hematol Oncol. 2021;14(1):102. Published 2021 Jun 30. doi:10.1186/s13045-021-01115-0
- Liu Y, Yan X, Zhang F, et al. TCR-T Immunotherapy: The Challenges and Solutions. Front Oncol. 2022;11:794183. Published 2022 Jan 25. doi:10.3389/fonc.2021.794183
About ACROBiosystems
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