T-Cell receptors therapy is a growing area of immuno-oncology with recent breakthroughs in clinical settings, thereby demonstrating its therapeutic potential in mitigating tumor development. So what do you know about T-Cell therapy? Read on! Dr. Erika von Euw from T-Cure Bioscience help us to understand it better.

Cancer immunotherapy is a validated and critically important approach for treating cancer and offering hope for curative responses in patients. Cancer immunotherapy relies on genetically engineered T-cells. T Cell Receptor Therapy (TCR-T) is a growing area of immuno-oncology with recent breakthroughs in clinical settings, thereby demonstrating his therapeutic potential in mitigating tumor development.

Earlier this month, Atlas Antibodies signed a collaboration agreement with T-Cure Biosciences Inc. for the development, manufacture, and supply of PrecisA Monoclonals for the treatment of solid tumors. T-Cure is developing TCR-T therapeutics targeting the Kita-Kyushu Lung Cancer Antigen 1 (KK-LC-1) for gastric, triple-negative breast cancer, cervical, lung, and other KK-LC-1 positive cancers. Under the terms of the agreement, Atlas Antibodies will provide the KK-LC-1 PrecisA monoclonal antibody for the companion diagnostic for clinical development. 

Read the press release: Atlas Antibodies & T-Cure Bioscience

T-Cure and T-Cell Receptor Therapy

Dr. Erika von Euw is the Senior Director of Translational Research at T-Cure Bioscience, Inc., Los Angeles. Her role focuses on expanding and developing key strategies to advance TCR-T preclinical programs in the clinic. We asked her 5 questions to help us better understand TCR-T, its challenges, strategies, and future applications.

Thanks for joining us, Erika! Could you tell us about your role and your scientific background?

Dr. Erika von Euw: I am the Senior Director of Translational Research at the biotech named T-Cure Bioscience, located in Los Angeles, CA, USA. My focus is to provide scientific leadership in areas of target discovery, TCR development, and translational science, working with multiple cross-functional teams. I also oversee preclinical development, companion diagnostics development, clinical operations, and external experts as appropriate to develop scientifically rigorous translational strategies.

Prior to working at T-Cure, I spent almost 12 years at UCLA, where I did my post-doc back in 2008-2010 to then become a junior faculty and finally an Assistant Professor. My Ph.D. was in immunology, specifically in a Dendritic Cell vaccine for melanoma patients at the University of Buenos Aires, Argentina. 

Q1. What is innovative about T-Cell Receptors Therapy?

Dr. Erika von Euw: Engineered TCR-T involves treating cancer with activated T-lymphocytes from the body. This is similar to CAR T-cell therapy. However, CAR T-cells were pioneered for B-cell leukemias and lymphomas and are less developed for solid tumors. TCR T-cells may prove to be a more effective option for solid tumors where intracellular antigens presented in MHC (not recognizable by CAR T-cells) can differentiate cancer cells from normal tissues.

Q2. The identification of relevant targets is one of the most critical aspects of TCR-T. What is your process for target selection?

Dr. Erika von Euw: I believe that target identification and validation of a tumor antigen is the most important step in the cell therapy field. In addition, target selection is a critical step in new agent development. Poorly selected antigens (e.g., with poor expression level or immunogenicity) are one of the primary reasons for preclinical study failure.

There are two major classes of tumor antigens that are targeted by TCR-T: (a) private antigens and (b) public shared antigens. The latter, public shared antigens, are common to multiple patients and are further split into two categories:

• Tumor-specific antigens (TSA), are found on cancer cells only, not on healthy cells.
• Tumor-associated antigens (TAA), have elevated levels in tumor cells, but are also expressed at lower levels in healthy cells.

Several key differences between TSAs and TAAs need to be carefully considered when selecting a target antigen (Table 2). 

Nowadays, we have many publicly available databases with DNA, mRNA, and protein data from normal and tumor tissues. So the first step is to identify the gene and look at the mRNA and protein in normal vs. tumor samples. Then explore the literature on the target. Lastly, the intellectual property and competitive landscape will define the go/no go if the target profile is good in terms of expression.

Did you know? 
”Immunotherapy is the fastest and most remarkable developing field which has generated new therapeutic options for solid tumor and blood cancer patients. As a result, cancer immunotherapy has been cited as the greatest scientific breakthrough of 2013! As such, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo, who discovered how to harness the body's immune system to fight cancer, highlighting the importance of research progress in the field of immunotherapy.” Couzin-Frankel J. 2013. 

Q3. What are the preclinical strategies to identify possible off-target-induced toxicity?

Dr. Erika von Euw: Off-target toxicity occurs when the TCR or CAR transduce T-cell population unexpectedly attacks an antigen other than the intended one or activates itself independently from their specificity.

One of the most useful strategies in cell therapy is to use normal cells and co-incubate them with the cells transduced with the specific TCR or CAR. It is essential to test normal cells from key organs (cardiovascular, liver, gastric, colon, etc.) and several donors to account for individual variability. For the off-target testing in the TCR field, the normal cells must be from the same haplotype that TCR is restricted to.   

There are also several novel mouse models based on an immunocompetent mouse model and a library of mouse tumor lines that are known to mimic specific types of human cancers. These models are widely used to identify possible off-target-induced toxicity.

Another method to identify off-target toxicity is the in silico and in vitro screening libraries for early detection of off-target toxicity due to the cross-reactivity of TCRs directed against unrelated peptides.

Reading tips: Preclinical Strategies to Identify Off-Target Toxicity of High-Affinity TCRs

Q4. Does TCR-T guarantee durable responses and survival for patients with terminal as well as earlier-stage cancer?

Dr. Erika von Euw: TCR-T cell therapies are only available in clinical trials and most of the clinical trials have been done in late-stage cancer patients. The data is encouraging with many patients responding to TCR-T therapies and this is especially true for the synovial sarcoma and melanoma patients responding to NY-ESO-1 TCR (D'Angelo SP. et al., 2018) and the cervical carcinoma patients after HPV-E7 TCR treatment (Nagarsheth NB. et al., 2021). In addition, adoptive T-cell therapy ADP-A2M4 targeting MAGE-A4 shows early activity in patients with advanced solid tumors (Hong DS. et al., 2020). 

Q5. What do you expect as the most significant breakthrough of TCR-T in the next future?

Dr. Erika von Euw: TCR T-cell therapy is a promising and growing area of cell immunotherapy. The future of these personalized therapies requires making the products more efficient and generally applicable in routine patient care. Various technical challenges have been overcome and I believe we can expect the promise of TCR T-cell therapy to be fully realized in the next 5 years. 

References

• Bourre' L. Targeting Tumor-Associated Antigens and Tumor-Specific Antigens, CrownBio (2019).
• Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science 342(6165):1432-3 (2013).
• D'Angelo SP, et al., Efficacy and safety of first-line Avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma: a preplanned interim analysis of a clinical trial. JAMA Oncol. 4(9):e180077 (2018).
• Hong DS et al., Phase I dose-escalation and expansion trial to assess the safety and efficacy of ADP-A2M4 SPEAR T cells in advanced solid tumors. Journal of Clinical Oncology 38:15_suppl, 102-102 (2020)
• Nagarsheth NB. et al., TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med 27, 419–425 (2021)
• Tsimberidou, AM., Van Morris, K., Vo, H.H. et al. T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors. J Hematol Oncol 14, 102 (2021)