How a “living drug” can cure fatal blood cancers
A 2021 research study conducted by the National Institutes of Health (NIH) found that the key to killing cancerous cells is allowing a period of rest for healthy cancer-fighting cells to mobilize and thrive.
As we age, our cells are more likely to acquire mutations, leading to a higher likelihood of developing cancer. Recently, scientists have found that defensive T-cells play a role in our adaptive immune response and can be reprogrammed to fight certain blood cancers [3].
One such blood cancer called acute lymphoblastic leukemia or ALL is a rapidly developing cancer of the white blood cells that commonly occurs in children [1]. While children have an excellent prognosis for this disease, and an 85% chance of being cured, the prognosis for adults is much poorer with their survival rate being 30% to 40% [7].
Many adult ALL patients also experience relapse, meaning that their cancer returns after it was cured through rigorous chemotherapy. The chance of relapsing is about 50% in adults and 10% for children [4]. Furthermore, recovery for adult relapse patients is extremely difficult. Continuing chemotherapy after relapse can be ineffective and extremely draining on a patient’s body.
However, there is hope for ALL patients due to a novel therapy called CAR-T cell therapy, which pioneer and leading oncologist Carl June describes as a “living drug” created from a patient’s own cells [3]. The therapy involves transforming a patient’s regular immune system T-cells into cancer-fighting CAR-T cells. These CAR-T cells are able to recognize specific proteins on tumor cells and kill them [6].
CAR stands for chimeric antigen receptor, which is a specific receptor engineered onto the patient’s T-cells [6]. Our bodies’ cells consist of receptors on their surfaces, which are similar to locks [6]. Cells also possess proteins or antigens that act as keys to fit in these locks and trigger processes inside target cells [6]. CARs mediate cancer cell death by recognizing and binding to antigens expressed on the surface of cancer cells [6]. After binding occurs, the CAR-T cells send out signaling proteins called cytokines to other parts of the immune system, resulting in more T-cells becoming activated [5]. These cells work together to cause inflammation in cancer cells, eventually leading to their death [5]. This innovative therapy takes advantage of fundamental biological principles to fight cancer growth in a more organic approach compared to traditional chemotherapy.
One issue with the treatment that scientists are trying to resolve is a phenomenon called T-cell exhaustion, which is when a patient’s modified T-cells stop recognizing the tumor cells [8]. The T-cells are no longer able to multiply in the patient’s body as intended by the treatment due to overstimulation [8]. When their environment becomes oversaturated with cancer cells, or if the T cells send false signals to target cells which aren’t cancer cells, the CAR-T cells become exhausted [8]. To investigate the issue of this exhaustion further, Dr. Evan W. Weber from the Stanford Cancer Institute at the Stanford School of Medicine led a research study focused on exhausted CAR-T cells with a team of researchers at the NIH [8].
Their 2021 study consisted of one group of CAR-T cells given a 4-day break after 7 days of continuous activation, while the other group received no break and remained activated for 11 days straight [8]. The “always on” cells received higher exhaustion scores while the rested cells received lower scores and were more effective in finding tumor cells in vivo after their break [8].
The 2021 NIH study discovered that giving engineered patient T-cells a period of rest as part of a novel treatment for blood cancers improved outcomes for killing cancer cells.
Dr. Weber’s team also analyzed the effect of a drug called dasatinib, which they used to activate the T-cells after they were engineered with CARs ex vivo [8]. Scientists gave exhausted CAR-T cells dasatinib for 4 days, then stopped administering it for 3 days and analyzed the result [8]. They discovered that the number of CAR T-cells in vivo increased, and were more efficient at targeting tumor cells compared to those that received the drug for 7 days straight [8].
Researchers who conducted this 2021 study highlight some of the work that still needs to be done before introducing this approach to treatment plans for cancer patients. Another issue is that while CAR-T cells are given a period of rest in a patient’s body, the tumor may be given time to grow without anything stopping it. Prompting researchers to experiment with allowing only a subpopulation of the CAR-T cells in the patient’s body a period of rest, so other cells can do the job of keeping the tumor cells in check [8].
While further research in this field is required, we now have a more promising way of treating fatal blood cancers in children and especially adults. As useful as our own body's T-cells are for everyday infections, introducing newly engineered cells into the body holds much promise for treating diseases that were previously believed to be incurable. Still, further research can be done to reduce the severity of side effects of this treatment on cancer patients. The potential for this therapy to replace the traditional approach of chemotherapy is significant for ultimately minimizing the pain and improving the quality of life for blood cancer patients.
About the Author: Riya Jariwala
Riya is a third-year Biochemistry and Molecular Biology Major on the pre-medicine track at UC Davis. She wrote this New York Times article during her UWP 102B class with Professor Amy Goodman-Bide because of her interest in cancer biology, which began after the loss of her older sister to leukemia. In the article, she delves into the possibility of CAR-T cell therapy for acute lymphoblastic leukemia. She recognizes the hardships that adult blood cancer patients face due to their often poor prognosis. Her goal is to educate other students about ongoing cancer prevention research, and inspire hope for curing rare cancers given the promise of targeted cell therapies. Outside of academics, Riya contributes to her community as a volunteer with Relief from Cancer and the American Cancer Society to raise awareness and funds for patient support programs. She also finds fulfillment in her role at River Pediatric Clinic, where she enjoys helping children in the greater Sacramento area receive the primary care they need.
References
Acute Lymphoblastic Leukemia (ALL). Yale Medicine. https://www.yalemedicine.org/conditions/acute-lymphoblastic-leukemia-all.
Immunotherapy | NorthShore. 2019. Northshoreorg. https://www.northshore.org/kellogg-cancer-center/our-services/immunotherapy/.
June C. 2019. A “living drug” that could change the way we treat cancer. TED. https://www.ted.com/talks/carl_june_a_living_drug_that_could_change_the_way_we_treat_cancer.
Leach, Isabelle. Relapse in Acute Lymphoblastic Leukaemia (All), media.leukaemiacare.org.uk/wp-content/uploads/Relapse-in-Acute-Lymphoblastic-Leukaemia-ALL-Web-Version.pdf. Accessed 29 Aug. 2023.
Portell CA. 2021 Jun 17. How Does CAR T-Cell Therapy Work in Treating Cancer? CancerNet. https://www.cancer.net/blog/2021-06/how-does-car-t-cell-therapy-work-treating-cancer#:~:text=When%20a%20CAR%20T%20cell%20comes%20in%20contact.
Print. CAR-T Cell Therapy Program - About CAR-T cell therapy. Mayo Clinic. https://www.mayoclinic.org/departments-centers/car-t-cell-therapy-program/sections/gnc-20405215.
Roberts, Kathryn G. “Genetics and Prognosis of All in Children vs Adults.” Hematology. American Society of Hematology. Education Program, U.S. National Library of Medicine, 30 Nov. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6245970/.
Weber EW, Parker KR, Sotillo E, Lynn RC, Anbunathan H, Lattin J, Good Z, Belk JA, Daniel B, Klysz D, et al. 2021. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science. 372(6537). doi:https://doi.org/10.1126/science.aba1786.