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Health and Disease

Efficacy of CAR-T cell Therapy in Patients with Hodgkin lymphoma who Relapse or Experience Primary Refractory Disease

CAR-T cell therapy shows promising results in cancer treatments, however, in terms of treating Hodgkin’s lymphoma it is considered an option when patients relapse or experience primary refractory disease. CAR-T cell therapy is considered a good alternative to regular treatment as the safety is high and, at the same time, it makes many patients respond to treatment.

Background

Chimeric antigen receptor (CAR) T-cell therapy is a novel form of treatment for primarily blood cancers. CAR-T cell therapies involve engineering individual patients’ T-cells to target specific cancer cells. First, blood is taken from a patient to acquire their T-cells. Secondly, CAR-T cells are produced in the lab where the CAR genes are inserted into the T-cells. Afterward, CAR proteins appear on the surface of the T-cells and they are then reproduced millions of times so that they can be infused into the patient. Then the goal for the CAR-T cells becomes binding to cancer cells to kill them (National Cancer Institute, 2019). This is as illustrated below in figure 1:

Figure 1: How CAR-T cell therapies work (National Cancer Institute, 2019).

Hodgkin’s lymphoma (HL) is a type of cancer that manifests itself in the lymphatic system and the cancer presents itself with supra-diaphragmatic lymphadenopathy meaning swollen lymph nodes above the diaphragm. The cancer cells are characterized as Hodgkin and Reed-Sternberg (HRS) cells. 

Additionally, it is one of the most prevalent cancer types in adolescents. The B-cell lymphoproliferative disorder can be divided into classical HL (cHL) and nodular lymphocyte-predominant HL (NLPHL), however, cHL accounts for over 90% of the cases, which is why it will be the main focus of this article. Though, one thing that all HL subtypes have in common is that they all share an immunophenotypic pattern of CD15+, CD30+ as well as CD45-, antigens that indicate Hodgkin’s lymphoma.

HL has various treatment options ranging from chemotherapy to radiotherapy. The treatments have high rates of curability, even in cases of a patient advancing through the stages of HL (Shanbhag & Ambinder, 2017).

When CAR-T cell therapy should be considered the favorable treatment option

Most cases of HL are sufficiently cured with first-line therapy. However, 15% of HL patients relapse or acquire primary refractory disease, which means they do not go into complete remission. The usual first-line therapy alternative is high-dose chemotherapy and autologous stem cell transplantation (aSCT). aSCT refers to capturing stem cells before going into treatment and injecting them back into the body following the treatment. Around 50% of individuals going through this treatment relapse after transplantation. The issues with the alternative treatment to aSCT are that allogeneic stem cell transplantation (alloSCT) results in high morbidity as well as mortality, even though it provides the most optimal chances for achieving sustained remission. alloSCT shares similarities with aSCT, however the difference in alloSCT is that stem cells are extracted from a donor instead to replace damaged stem cells as a result of radiation or chemotherapy (Ramos et al., 2020).

In July 2021 in America, the treatment for early-stage cHL was comprised of doxorubicin (or adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD), a series of chemotherapies. The former is the most common front-line therapy there is, but this form of treatment does not come without side effects. Generally, cHL patients will be at risk for long-term complications such as cardiopulmonary toxicities, secondary malignancies, and quality of life (QoL) impairment. The latter is, among other things, why the spotlight has been on improving the side effects of being treated with front-line therapy. The first, second, and third line of treatment is shown below in figure 2 (Mohty et al., 2021)

Figure 2: Lines of treatment for cHL in advanced stages (Mohty et al., 2021).

When the time finally comes to consider CAR-T cell therapy for treating cHL the potential side-effects and the efficacy of CAR-T cell therapy must be taken into consideration.

CAR-T cell therapy has one significantly dangerous side effect, which is cytokine release syndrome (CRS) (National Cancer Institute, 2019). CRS is a condition where an abundance of cytokines are released as a result of immunotherapies like CAR-T cell therapy. The danger lies in the cytokines’ function. They are meant to maintain a healthy amount of blood cells and immune cells, but this becomes difficult when the body is overloaded with cytokines (Cleveland Clinic, 2022). The more cancer cells there are in the body the more likely it is to experience CRS when treated with CAR-T cells. Mild courses of CRS are mostly controllable with first-line therapies and more serious cases of CRS are becoming easier to treat as well, as more experience with CAR-T cell therapies is gained through research. CAR-T cell therapy becomes ineffective when it has to deal with solid tumors. This is especially true for tumor heterogeneity, which is the diversity of cancer cells in a tumor. The latter is due to the fact that solid tumors can vary a lot when it comes to the individual person and sometimes this applies to one patient’s body itself. The molecular diversity in the solid tumors makes it incredibly difficult to treat because the molecular diversity can contribute to the CAR-T cells being unable to function properly (National Cancer Institute, 2019).

The magic of CAR-T cell therapy in cHL shines through when the patient has relapsed or has experienced primary refractory diseases. A study shows that responses to Anti-CD30 CAR-T cell therapies are superior to bendamustine in patients who have previously been treated with bendamustine. In addition to this, when the CAR-T cell therapy was used following fludarabine-containing lymphodepletion regimens it resulted in 59% of complete responses out of 32 patients. The most prevalent toxicities were grade 3 or higher hematologic adverse events. The overall response rate of patients that received fludarabine-based lymphodepletion was 72% (Ramos et al., 2020).

The bottomline is that CAR-T cell therapy should be done when patients are relapsing or experiencing refractory diseases in relation to cHL, because the safety of use is incredible while also maintaining high response rates.

Daniel Godiksen, Youth Medical Journal 2022

References

Cleveland Clinic. (2022, April 7). Cytokine Release Syndrome: Symptoms, What It Is & Treatment. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/22700-cytokine-release-syndrome

Mohty, R., Dulery, R., Bazarbachi, A. H., Savani, M., Hamed, R. A., Bazarbachi, A., & Mohty, M. (2021). Latest advances in the management of classical Hodgkin lymphoma: the era of novel therapies. Blood Cancer Journal, 11(7), 1–10. https://doi.org/10.1038/s41408-021-00518-z

National Cancer Institute. (2019, July 30). CAR T Cells: Engineering Immune Cells to Treat Cancer. National Cancer Institute; Cancer.gov. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

Ramos, C. A., Grover, N. S., Beaven, A. W., Lulla, P. D., Wu, M.-F., Ivanova, A., Wang, T., Shea, T. C., Rooney, C. M., Dittus, C., Park, S. I., Gee, A. P., Eldridge, P. W., McKay, K. L., Mehta, B., Cheng, C. J., Buchanan, F. B., Grilley, B. J., Morrison, K., & Brenner, M. K. (2020). Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma. Journal of Clinical Oncology, 38(32), 3794–3804. https://doi.org/10.1200/jco.20.01342

Shanbhag, S., & Ambinder, R. F. (2017). Hodgkin lymphoma: A review and update on recent progress. CA: A Cancer Journal for Clinicians, 68(2), 116–132. https://doi.org/10.3322/caac.21438

Sterner, R. C., & Sterner, R. M. (2021). CAR-T Cell therapy: Current Limitations and Potential Strategies. Blood Cancer Journal, 11(4), 1–11. https://doi.org/10.1038/s41408-021-00459-7

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