Introduction
Cancer, a multifaceted and often devastating disease, affects millions of lives globally each year. Despite remarkable progress in medical science, the journey towards finding more effective and less detrimental treatments continues. This malady, characterized by the uncontrolled growth and spread of abnormal cells, represents a complex biological anomaly that disrupts the normal lifecycle of cells within the body. Under typical conditions, cellular growth and division are tightly regulated processes that maintain tissue health and function. However, in the case of cancer, these regulatory mechanisms fail. This failure leads to the proliferation of cells that no longer adhere to the body’s natural constraints, growing and dividing in an unchecked manner. These cancerous cells can invade and destroy healthy tissue, including vital organs, significantly impairing bodily functions and, if left untreated, can lead to fatal outcomes. Immunotherapy, with a special spotlight on Chimeric Antigen Receptor T-cells (CAR-T) cell therapy, has emerged as an innovative approach in this journey, offering renewed hope to those battling cancer.
Yang et al. (2020)
The science of CAR-T cells
At the forefront of immunotherapy lies CAR-T therapy. CAR-T cell therapy involves taking a patient’s immune cells (T cells), and engineering them in a laboratory to produce a special structure called a Chimeric Antigen Receptor (CAR). This structure enables the T cells to recognize and attack cancer cells by binding to specific proteins on the cancer cells’ surface. Once these modified T cells are infused back into the patient, they seek out and destroy cancer cells.
Yang et al. (2020)
Switchable CAR-T cells: an innovation
Building on CAR-T cell therapy’s success, scientists have developed sCAR-T cells, an advanced version with an added “switch” feature. This innovative approach allows precise control over when and where the T cells are activated, aiming to target cancer cells more accurately and reduce potential side effects. By enhancing the safety and effectiveness of CAR-T cell therapy, especially against hematological malignancies, sCAR-T cells represent a significant step forward in personalized cancer treatment.
Yang et al. (2020)
The limitations with traditional CAR-T cells
Traditional CAR-T cell therapies, while powerful against cancer, can activate without strict control, leading to excessive immune responses. This unregulated activity can cause severe side effects, including cytokine release syndrome (CRS), where a flood of immune signals leads to high fever, low blood pressure, and potentially life-threatening complications. Additionally, there’s the risk of “on-target, off-tumor” effects, where CAR-T cells attack healthy cells that share antigens with cancer cells, causing damage to normal tissues.
Wu et al. (2015)
The technology behind the safety of switchable CAR-T cells
Switchable CAR-T cells are engineered to remain inactive until a specific, externally administered molecule —a “switch”— activates them. This switch is a biologically designed molecule that binds to the engineered receptor on the CAR-T cell. Only in the presence of this switch molecule can the CAR-T cells become active, allowing for targeted cancer cell destruction. This controllable activation mechanism ensures that CAR-T cells can be turned on and off in response to the patient’s needs, significantly minimizing unintended attacks on healthy cells and reducing the risk of CRS.
Moreover, the dose of the switch molecule can be adjusted, providing doctors with the ability to fine-tune the therapy’s intensity according to the tumor’s response and the patient’s tolerance. This level of control makes switchable CAR-T therapy a highly personalized and adaptable treatment option, promising greater safety and efficacy in battling not only blood cancers but also solid tumors, which have been more challenging to treat with traditional CAR-T cells.
Yu et al. (2019)
Engineering and administration of sCAR-T cells:
To make switchable CAR-T cells, scientists modify certain immune cells (T cells) to recognize cancer cells in a controllable way. They do this by adding a special marker to antibodies (proteins that can bind to specific targets) that only the modified T cells can recognize. This marker is like a unique key that fits into a lock only on the engineered T cells. The T cells are then able to attack cancer cells when they’re “switched on” by a special substance that acts as a bridge between the T cells and the cancer cells.
Four key steps are necessary to perform sCAR-T cell therapy:
- Preparation and infusion: The patient undergoes a preparation phase that may include chemotherapy to make the body more receptive to the CAR-T cells. Following this, the engineered switchable CAR-T cells are infused into the patient’s bloodstream.
- Activation with the switch: After the CAR-T cells are infused, a specially designed switch molecule is administered. This switch is key to activating the CAR-T cells so they can target and attack cancer cells. The timing of switch administration is crucial and is typically given on a schedule that may include multiple doses to optimize the cells’ activity against the cancer.
- Monitoring and adjustments: Patients are closely monitored following the infusion for any signs of side effects, as well as the treatment’s effectiveness. This includes regular medical checks and possibly additional doses of the switch molecule to ensure the CAR-T cells are active only when needed. This control mechanism helps to reduce the risk of side effects associated with traditional CAR-T cell therapies, such as CRS.
- Follow-up for long-term response: After the initial treatment and activation phase, patients may undergo follow-up sessions to assess the long-term effectiveness of the therapy. This might include measuring the persistence of CAR-T cells in the body and their memory response, which is crucial for preventing cancer recurrence.
Viaud et al. (2018)
Clinical trials
In a groundbreaking study by Calibr at Scripps Research, scientists tested the efficacy of switchable CAR-T cells on 9 patients with B cell malignancies. Calibr’s first-in-human clinical trial of a switchable CAR-T cell therapy showcased an impressive overall response rate of 78%, with 67% achieving complete response. This trial emphasized not only the potential efficacy of these cells in treating cancer but also highlighted their safety, showing a lower incidence of severe side effects commonly associated with CAR-T cell therapies, such as CRS and immune effector cell-associated neurotoxicity syndrome (ICANS). Importantly, the ability to adjust the dosage of the switch molecule (SWI019) allowed for better management of CRS and ICANS, showing a significant advancement over existing CAR-T therapies in terms of safety and control.
https://www.scripps.edu/news-and-events/press-room/2022/20220921-calibr-cart.html
In another study on a switchable CAR-T therapy for acute myeloid leukemia (AML), 3 patients were treated with varying doses of UniCAR-T cells and the targeting module TM123. All patients showed a clinical response; one had partial remission, and two achieved complete remission with incomplete hematologic recovery. No dose-limiting toxicities were observed, and side effects were generally mild, including Grade 1 CRS in two patients that subsided quickly. This demonstrates the potential of switchable CAR-T therapy to effectively treat AML with manageable side effects.
Wermke et. al (2021)
Ethical concerns
Switchable CAR-T cell therapies raise significant ethical considerations essential for their successful transition into clinical practice. These concerns encompass safeguarding the safety and welfare of patients and research participants, given the potent and occasionally unpredictable character of CAR-T treatments. Additionally, ensuring equitable access to this therapy is imperative, tackling the obstacle of providing these potentially life-saving treatments to diverse socioeconomic groups amidst challenges such as high costs and limited healthcare infrastructure. Lastly, effectively managing public and patient expectations requires transparent communication regarding the current capabilities and limitations of these therapies, mitigating misinformation and unrealistic expectations while fostering a pragmatic comprehension of the treatment’s potential outcomes and risks.
Imbach et al. (2018)
Conclusion and future directions
Switchable CAR-T cell therapies represent a transformative advancement in cancer treatment, promising more controlled and safer options for patients. The innovation of a switch mechanism allows for precise targeting of cancer cells, potentially reducing side effects like CRS. Clinical trials show promising results, with significant response rates and manageable side effects. Ethical considerations, including patient safety, equitable access, and managing expectations, are central to their development and use. Future directions may entail extending these therapies beyond blood cancers to include solid tumors, as well as enhancing accessibility and affordability for all patients.
References
Yang, P., Wang, Y., Yao, Z., Gao, X., Liu, C., Wang, X., Wu, H., Ding, X., Hu, J., Lin, B., Li, Q., Li, M., Li, X., Chen, X., Qi, W., Li, W., Xue, J., & Xu, H. (2020). Enhanced safety and anti-tumor efficacy of switchable dual chimeric antigen receptor-engineered T cell against solid tumor through a synthetic bifunctional PD-L1-blocking peptide. Journal of the American Chemical Society. https://doi.org/10.1021/jacs.0c08538.
Wu, C.-Y., Roybal, K. T., Puchner, E. M., Onuffer, J., & Lim, W. A. (2015). Remote control of therapeutic T cells through a small molecule–gated chimeric receptor. In Science (Vol. 350, Issue 6258). American Association for the Advancement of Science (AAAS). https://doi.org/10.1126/science.aab4077
Yu, S., Yi, M., Qin, S., & Wu, K. (2019). Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Molecular Cancer, 18, 125. https://doi.org/10.1186/s12943-019-1057-4
Viaud, S., Ma, J. S. Y., Hardy, I. R., Hampton, E. N., Benish, B., Sherwood, L., & Young, T. S. (2018). Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory. Proceedings of the National Academy of Sciences of the United States of America, 115(46), E10898-E10906. https://doi.org/10.1073/pnas.1810060115
Wermke, M., Kraus, S., Ehninger, A., Bargou, R. C., Goebeler, M.-E., Middeke, J. M., Kreissig, C., von Bonin, M., Koedam, J., Pehl, M., Bornhäuser, M., Einsele, H., Ehninger, G., & Cartellieri, M. (2021). Proof of concept for a rapidly switchable universal CAR-T platform with UniCAR-T-CD123 in relapsed/refractory AML. Blood, 137(22), 3145–3148. https://doi.org/10.1182/blood.2020009759
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