Invisible Superheroes: The Marvel of Cancer Immunotherapy

By: Raven Garcia

Much like superheroes who confront their greatest villains, the immune cells within our bodies embark on a heroic mission in the formidable battle against cancer. One of their toughest foes is acute myeloid leukemia (AML), a highly challenging cancer to treat. AML is an aggressive disease that abnormally accelerates the production of immature white blood cells, instigating an internal war and overtaking the healthy blood cells.¹ Chemotherapy, a prevalent treatment for AML, functions by eliminating the abnormal (highly proliferative) cancer cells. Unfortunately, AML occasionally demonstrates Charles Darwin’s famous principle of ‘survival of the fittest’. After chemotherapy these remaining cancer cells defy the odds, becoming stronger than ever and resistant to subsequent chemotherapy treatments.^2,3 In the face of such defiance, immunotherapy — a groundbreaking approach that equips our immune system to better seek and destroy cancer cells — offers new hope. That is where the microscopic superheroes step up to the challenge.

The Role of T cells: The Microscopic Superheroes

Beyond the surface of skin lies a realm of marvels, where immune cells operate as vigilant heroes, maintaining the functionality and equilibrium within healthy functioning bodies. Despite being invisible to the naked eye, numerous specialized superheroes inhabit the human body, each with unique shapes, sizes, and functions. T cells are one of the most crucial superheroes aiding the body’s defense system, acting as attentive guardians against invading pathogens. These remarkable T cells possess the ability to recognize threats through their T cell receptors (TCRs), which bind to specific antigens presented by other cells or on the surface of diseased cells, such as cancer. Once activated, T cells become the leaders of an immune alliance, orchestrating a heroic response by signaling to other immune cells to ensure swift and effective protection. This signal ignites a call to fellow immune allies, prompting them to multiply, enhance their powers, or migrate to the site of the disease. Thus, T cells act as the supreme commanders, assembling an immune army to safeguard the body’s health and tirelessly work to do so.

Can γδ T cells Overcome their Kryptonite?

However, like all superheroes, T cells have their own kryptonite: cancer. One of the challenges they encounter is that cancer cells employ a clever disguise by altering their surface markers, effectively camouflaging them from T cells. Cancer cells effectively blend into the crowd of healthy cells through this deceptive facade. This trickery confuses T cells, impairing their ability to recognize and gather their immune cell army, thereby allowing the disease to spread undetected throughout the body.

Amongst the diverse subclasses of crime-fighting T cells, gamma delta T (γδ) cells display a unique potential compared to their alpha-beta (αβ) T cell counterparts. Armed with natural killer (NK) receptors, γδ T cells can rapidly recognize stress-induced proteins, thereby recognizing the hidden villains lurking in the body.⁴ Moreover, γδ T cells are independent superheroes that do not rely on the major histocompatibility complex (MHC) to do their job. The MHC acts like a surveillance system that displays protein fragments to help immune cells recognize potential dangers. While αβ T cells depend on this system to identify threats, γδ T cells have their own super senses. This autonomous surveillance system equips these cells to rapidly respond to emerging threats, making them a valuable asset in the ongoing battle against cancer, especially when traditional MHC methods fail to detect hidden cancer cells. Unfortunately, due to its low abundance, and difficulty reproducing γδ T cells into sufficient numbers for drug implementation, these cells were once unlikely to make it to the big leagues of cancer immunotherapy. However, like any superhero, some artistry or modification is often required to enhance their superpowers. After all, what is Iron Man without his suit? What is Spider-Man without the spider venom?

γδ T cells Transformed: The Superpowers of DOT Cells 

Given the unique functions of γδ T cell crime fighters in cancer, these cells have the potential to be utilized in therapeutic approaches. Therefore, a team of research scientists has implemented a groundbreaking endeavor. They developed a method to extract γδ T cells from the body and enhance the most lethal γδ T cell subset (Vδ1).^5,6 This methodology involves a stepwise addition of a serum, crafted by Correia et al., containing cell signaling proteins, cytokines and TCR agonists, that stimulate the expansion of Vδ1 T cells, creating a powerful therapeutic superhero army, now termed Delta One T cells (DOT cells).^5–7

What makes DOTs different from the general γδ T cells? The answer is within their arsenal. Once stimulated by this innovative serum, the almighty DOT cells come equipped with a larger receptor repertoire (Figure 1), enhancing their ability to recognize and attack AML cancer cells.⁷ These receptors act as the ‘weaponry’ that equips DOT cells with a superior ability to recognize and respond to threats. Having a larger repertoire of receptors allows DOT cells to identify more AML cancer cells and, in turn, unleash a more potent attack than their γδ T cell counterparts.⁷ For example, once these receptors bind to their targets, they enable the DOT cells to unleash high levels of granzymes and perforin, the toxic proteins that destroy cancer cells. In this way, the enhanced receptor repertoire doesn’t just aid in detection—it directly boosts the cells’ ability to execute a stronger attack.⁸ This unique blend of enhanced recognition and potent weaponry makes DOT cells powerful allies in the battle against AML, offering hope against this challenging cancer. Just as Peter Parker transformed into Spider-Man with the bite of a radioactive spider, γδ T cells undergo a metamorphosis into DOT cells with the infusion of this specialized serum, emerging as potential champions in the fight against AML.

DOT Cells vs. Other Immunotherapy Superheroes 

DOT cells are not the only transformed superheroes on the market of cancer immunotherapy. Additional therapies such as chimeric antigen receptor (CAR) T cell therapy have also been implemented and have shown promising results in leukemia and lymphoma cancers.⁹ This man-made therapy involves genetic manipulation to enhance the T cell’s ability to recognize and target cancer cells. Unlike DOT cells, which are stimulated to possess a wide variety of receptors, CAR-T cells are genetically engineered to express one artificial receptor –The CAR– that recognizes a given antigen on the surface of cancer cells. These CAR-T cells are typically derived from the patient’s T cells and are expanded ex-vivo, enhancing targeting accuracy and effectiveness. However, despite their unwavering precision, in the case of AML, the only promising targetable antigens are present in healthy cells.¹⁰ Therefore, these CAR-T cells can mistakenly attack the healthy cells residing in the body, leading to toxicity. While CAR-T cell therapy has proven effective in other leukemias and lymphomas, its high cost, complexity of production, and potential cytotoxicity highlight the need to explore alternative therapies like DOT cells. Prioritizing the improvement of DOT cells and how to enhance their therapeutic powers could be pivotal in the fight against AML. 

The Great Responsibility of Research: Understanding the Powers of Immunotherapy Superheroes

Researchers have found compelling preclinical evidence that DOT cells display remarkable specificity, effectively targeting AML cells while sparing normal, healthy myeloid cells.⁷ This targeted action contributes to the potential for a safer and more effective immunotherapy for patients with AML. As a result, clinical trials have begun investigating GDX012,¹¹ a novel therapy based on DOT cells, for patients with relapsed or refractory AML. While these superpowers are impressive, it is crucial to note that immunotherapy works for some but not all patients. Numerous factors can still affect the efficacy and safety of these treatments.

Even superheroes, with incredible powers, need assistance. Just as Iron Man relies on JARVIS for support and guidance, DOT cells depend on researchers to maximize their abilities and minimize potential challenges. One prospective challenge in DOT cell therapy is donor variability, which can influence the effectiveness of the treatment from one person to another. This variability is like trying to fit a custom suit to many different body types—while it might fit some individuals perfectly, for others, adjustments are needed to ensure the best outcome. Similarly, each donor’s cells may vary in their ability to interact with AML cells. Therefore to optimize their impact, it’s essential to understand exactly how these cells interact with and recognize AML cells.⁸ Once these mechanisms are fully understood, researchers can amplify the effectiveness of DOT cells and assess treatment outcomes by identifying potential biomarkers. Overall, researchers are key players in this journey, striving to learn how to harness the incredible potential of DOT cells effectively. 

The current immunotherapies on the market today bear the weight of the profound truth: With great power holds great responsibility. Researchers hold the responsibility of assessing the challenges of immunotherapy to ensure that these innovative treatments can meet the unique needs of each patient. Numerous factors such as individual variations in patients’ immune systems, the complexity of the tumor microenvironment, and the potential for immune-related toxicities all contribute to the challenges immunotherapy faces. Continued research is essential to harness the superpowers of immunotherapy such as DOT cell therapy. By understanding the intricacies of these therapies, researchers can optimize the efficacy and minimize adverse effects, ultimately bringing us closer to a future where cancer can be managed more effectively. These researchers may be the greatest superheroes of all, working to unravel the unknowns and lead the quest to expose immunotherapy’s full potential, ultimately advancing patient outcomes in the battle against cancer.

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Further reading

1. Pimenta, D. B. et al. The Bone Marrow Microenvironment Mechanisms in Acute Myeloid Leukemia. Front Cell Dev Biol 9, (2021). ↩︎
2. Zhang, J., Gu, Y. & Chen, B. OncoTargets and Therapy Dovepress Mechanisms of drug resistance in acute myeloid leukemia. Onco Targets Ther 12–1937 (2019). ↩︎
3. Patel, A. et al. Outcomes of Patients With Acute Myeloid Leukemia Who Relapse After 5 Years of Complete Remission. Oncol Res 28, 811 (2021). ↩︎
4. Mensurado, S., Blanco-Domínguez, R. & Silva-Santos, B. The emerging roles of γδ T cells in cancer immunotherapy. Nat Rev Clin Oncol 20, 178–191 (2023). ↩︎
5. Correia, D. V. et al. Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells. Blood 118, 992–1001 (2011). ↩︎
6. Almeida, A. R. et al. Delta One T Cells for Immunotherapy of Chronic Lymphocytic Leukemia: Clinical-Grade Expansion/Differentiation and Preclinical Proof of Concept. Clin Cancer Res 22, 5795–5804 (2016). ↩︎
7. Di Lorenzo, B. et al. Broad Cytotoxic Targeting of Acute Myeloid Leukemia by Polyclonal Delta One T Cells. Cancer Immunol Res 7, 552–558 (2019). ↩︎
8. Mensurado, S. et al. CD155/PVR determines acute myeloid leukemia targeting by Delta One T cells. Blood 143, 1488–1495 (2024). ↩︎
9. Sheikh, S., Migliorini, D. & Lang, N. CAR T-Based Therapies in Lymphoma: A Review of Current Practice and Perspectives. Biomedicines 2022, Vol. 10, Page 1960 10, 1960 (2022). ↩︎
10. Atilla, E. & Benabdellah, K. The Black Hole: CAR T Cell Therapy in AML. Cancers (Basel) 15, (2023). ↩︎
11. Tekada. A Study of GDX012 in Adults with Relapsed or Refractory Acute Myeloid Leukemia. ClinicalTrials.gov. (2023). NCT05886491. ↩︎