In the previous article from the series, we introduced the core principles of CAR-T cell treatment for cancer therapy and described the underlying design principles, pros and cons, and differences between each of the currently available five generations of CAR-T molecule design. In this issue of “Decoding Gene and Cell Therapy“, we will introduce some real world use-cases for CAR-T cell therapy.
What types of cancer can be cured?
1. Acute Lymphoblastic Leukemia (ALL)
Acute lymphocytic leukemia, or ALL for short, is the most common form of cancer in children, and the recurrence of this disease is the leading cause of death of children with cancer. Therefore, the initial development of CAR-T technology was accompanied by a great number of clinical studies all revolving around the treatment of ALL. Dr. Stephan Grupp, a world-renowned pediatric oncologist, is one of the many pioneers of this type of research, having initiated the first trial for pediatric ALL CAR-T cell therapy at the Children’s Hospital of Philadelphia in 2012. Including the case of Emily Whitehead, which was described back in our previous article, the volunteers who received the early CAR-T trial were all patients afflicted with ALL who had relapsed or could not be cured with existing conventional therapies. In one of the trials involving 30 patients, Dr. Stephan Grupp injected CD-19-targeted CAR T cells into patients and successfully eliminated cancer cells in 27 of those patients, with many of those patients receiving subsequent long term treatment with no sign of cancer recurrence [1].
The success of early trials such as from Grupp’s lab, laid the foundation for larger-scale CAR-T clinical trials. Novartis started their own CAR-T therapy trial for children and adolescents with ALL back in 2012. Experimental data from that trial showed that many patients were in complete remission and had no signs of recurrence for a long time, leading to the approval of Novartis’ CAR-T product, Kymriah, in 2017 by the US Food and Drug Administration (FDA). In a very rare case for anti-cancer drug approvals, the drug was first approved for use in children before being approved to adults; however, this did not mean that the CAR-T therapy Kymriah cannot be used to treat adult cancer patients.
2. Diffuse large B-cell lymphoma (DLBCL)
Non-Hodgkin lymphomas, or NHL for short, is a general term for a group of common independent cancer diseases among which diffuse large B-cell lymphoma (DLBCL) is the most common, accounting for almost 1/3 of all NHL cases.
In 2017, the Journal of Clinical Oncology reported a CAR-T trial conducted by the National Cancer Research Institute for adult patients with advanced diffuse large B-cell lymphoma [2]. Among the 15 patients who received CD-19-targeted CAR-T cell therapy, 8 cases achieved complete remission, and 4 cases achieved partial remission. Subsequently, a larger clinical trial conducted by Kite Pharmaceuticals confirmed the effectiveness of CD-19 targeting CAR-T therapy in treating B-cell lymphoma. Its CAR-T product Yescarta, was approved for use in October of the same year, the first CAR-T therapy for specific non-Hodgkin’s lymphoma.
3. Peripheral T-cell Lymphoma (PTCL)
Peripheral T-cell Lymphoma is a heterogeneous group of aggressive non-Hodgkin’s lymphoma, accounting for 10-15% of all NHL cases, and is more challenging to treat than the previously covered DLBCL. The five-year survival rate of patients after diagnosis hovers at only 24%, with the 10-year survival rate being only 10%.
In 2016, iCell announced that its CD4CAR, for treating Peripheral T-cell Lymphoma, was granted an orphan drug designation by the FDA [3]. Unlike the two CAR-T products mentioned before, the target protein for this drug candidate is CD4 instead of CD19. CD4 is expressed in most mature T-cell lymphomas, making it a promising target for the treatment of PTCLs. Three years after iCell’s CAR-T product was qualified as an orphan drug, the famous Blood Journal (Blood) reported the first clinical trial of CD4 CAR-T cell therapy for Peripheral T-cell Lymphoma, which verified that CD4 CAR-T cells were effective and safe for patients with T-cell lymphoma [4].
4. Pancreatic Ductal Adenocarcinoma (Pancreatic Ductal Adenocarcinoma, PDAC)
Pancreatic cancer is known as the “king of carcinoma” in the field of tumors, with Pancreatic Ductal Adenocarcinoma being the most common type of pancreatic cancer with an incidence rate accounting for 80-90% of all pancreatic cancer. It is also the fourth most common cause of death in humans afflicted with solid tumor cancers, with the five-year survival rate of patients suffering from Pancreatic Ductal Adenocarcinoma being less than 5%.
Although there is still no CAR-T product specifically for Pancreatic Ductal Adenocarcinoma, studies have shown that potential CAR-T therapies are expected to use the CEACAM7 target of Pancreatic Ductal Adenocarcinoma to cure the cancer successfully, as CEACAM7 targets can be expressed in large amounts in Pancreatic Ductal Adenocarcinoma but with little to no expression in other parts of the gastrointestinal tract. This makes it possible to become a key specific target for CAR-T therapy development in treating Pancreatic Ductal Adenocarcinoma. In a preclinical model reported in the Journal of Clinical Cancer Research, researchers found that CAR-T cells targeting CEACAM7 can effectively kill CEACAM7-expressing cells in Pancreatic Ductal Adenocarcinoma cultures, thereby effectively suppressing pancreatic cancer. Development [5].
5. Multiple Myeloma (MM)
Multiple Myeloma is the second-most frequent hematological malignancy in the world, especially among populations over the age of 40, with particularly prevalence in people over the age of 60. As the problem of the aging population in the world intensifies, the demand for MM treatment is becoming more and more urgent.
B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. In 2015, Legend Biotech, a subsidiary of GenScript Biotech, together with the Second Affiliated Hospital of Xi’an Jiaotong University, jointly carried out a CAR-T clinical study targeting BCMA. The results showed that in 35 patients with relapsed or refractory Multiple Myeloma, the therapy showed a 100% objective remission rate, of which 14 patients had a complete remission, with a total remission rate of nearly 40%. The U.S. FDA then awarded Legend Biotech’s CAR-T therapy with a breakthrough therapy designation in December 2019 to treat patients with multiple myeloma. The US FDA accepted the priority review of this therapy’s biological product license application.
Conclusion: Sprinting ahead, the future of CAR-T
From Emily Whitehead’s successful treatment into complete cancer remission, to the gradual and continual approval of more and more novel CAR-T products and therapies, CAR-T as a method of immunotherapy has come a long way from being merely a concept written about in scientific papers, and has been translated successfully into a real-world setting. This miraculous development of CAR-T has also attracted the attention of domestic, large-scale pharmaceutical companies and R&D institutions worldwide.
However “ever rose has its thorns”, and CAR-T therapy likewise has its own set of side-effects and toxicities that must be addressed.” [6]. For example, some CAR-T treatments may trigger Cytokine Release Syndrome leading to a high fever and a sudden drop in blood pressure; they may also cause neurotoxicity which causes headaches, convulsions, and changes in consciousness. In addition, some cancer patients will experience disease recurrence due to the down-regulation of target antigen targets after starting CAR-T cell therapy.
These pressing issues have also accelerated the exploration of new tumor targets and the development of newer, less side-effect causing CAR-T products. This “Decoding Gene and Cell Therapy” series will continue to track the latest breakthroughs and progress made in the CAR-T cell therapy field. As the field continues to develop alongside technological advancements and research breakthroughs across the various fields of the life sciences, CAR-T will continue to stand the test of time and birth even more miraculous cancer clinical miracles as we unlock more of its potential.
Just how far can CAR-T run on the proverbial cancer therapy development’s race? Let us wait and see.
Reference
[1] Maude, Shannon L., et al. “Chimeric antigen receptor T cells for sustained remissions in leukemia.” New England Journal of Medicine 371.16 (2014): 1507-1517.
[2] Kochenderfer, James N., et al. “Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor.” Journal of clinical oncology 33.6 (2015): 540.
[3] The ASCO Post, “FDA Grants Orphan Drug Designation to CD4CAR for the Treatment of Peripheral T-Cell Lymphoma” achieved at https://ascopost.com/News/43829
[4] Zhang, Hongyu, et al. “First-in-Human CD4 CAR Clinical Trial on Peripheral T-Cell Lymphoma.” (2019): 2881-2881.
[5] Raj, Deepak, et al. “CEACAM7 Is an Effective Target for CAR T-cell Therapy of Pancreatic Ductal Adenocarcinoma.” Clinical Cancer Research 27.5 (2021): 1538-1552.
[6] American Cancer Society, “CAR T-cell Therapy and Its Side Effects” achieved at https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/car-t-cell1.html
