The approval of two cell-based gene therapies in 2017 for the treatment of children and young adults with acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma, has been heralded as a transformational approach to cancer therapy, as well as a major advancement in the treatment of hematological malignancies, offering potentially life-saving options for patients for whom other treatments have failed1, 2 .
A form of cancer immunotherapy, chimeric antigen receptor T-cell therapy, or CAR-T, typically involves a multi-stage process in which the patient’s T cells are extracted from their blood and sent to a laboratory where the DNA of the chimeric protein is inserted into the cells. The genetically engineered cells are then returned to the cancer center and infused back into the patient’s bloodstream, where the newly programmed cells multiply, target, and kill the cancer3, 4.
What has made CAR-T so remarkable are its dramatic success rates in producing long-term remissions in patients whose cancers have relapsed or become resistant to traditional therapies. In January, 2018, the American Society of Clinical Oncology (ASCO) named CAR-T as the treatment advance of the year4.
Currently Approved Therapies
ALL is the most common cancer among children in the U.S., with more than 3,000 new cases diagnosed each year5. Although current chemotherapy regimens cure more than 80% of ALL patients, prior to the introduction of a novel CAR-T therapy, those children and young adults who didn’t respond to treatment and/or relapsed after stem cell transplantation and/or remission, had very poor prognoses, with few treatment options remaining other than hospice care6. In a pivotal study of the therapy in this subset of ALL patients, the 3-month complete remission rate was 83% and the probability of survival was 89% at 6 months--a paradigm-shifting outcome for patients with previously little hope of surviving their disease7, 8, 9.
Equally significant has been a CAR therapy approved for the treatment of Aggressive Diffuse Large B-Cell Lymphoma (DLBCL), a form of non-Hodgkin’s lymphoma. In its pivotal trial, CAR cell therapy demonstrated an 82% success rate in reducing tumor size and a complete response rate of 54%10. At 18 months the study participants’ overall survival rate, considered the gold standard for a cancer treatment, was 52%, raising the possibility that CAR-T might be a cure for DLBCL10, 11.
CAR-T’s success in treating hematological cancers is not without its downsides. While initial response rates have been high, some longer-term studies have shown significant relapse rates, particularly in patients with the highest disease burden12. Serious adverse reactions and side effects have also been problematic3. Chief among them is cytokine release syndrome (CRS), a potentially fatal condition in which proteins called cytokines go into overdrive fighting the cancer cells, resulting in dangerously high fevers, plummeting blood pressure, fatigue, headache, chills, and an abnormally rapid heart rate3, 13, 14. Patients whose disease has progressed more are particularly vulnerable to CRS.
For patients with less serious CRS, clinicians are able to manage the symptoms with supportive therapies, including the use of an anti-inflammatory drug with a specific indication for the treatment of CAR-T induced CRS13, 14. Other potentially serious side effects of CAR-T include
- Neurotoxicity, a series of neurological symptoms that include delirium13, 14
- Risk of infections due to the loss of pathogen-killing antibodies13, 14
- Tumor Lysis Syndrome, a life-threatening condition caused by tumor cells breaking down in the body13
- Potentially fatal allergic reactions due to severe immune responses13
Further investigation is needed to better understand CRS and neurotoxicity in patients treated with CAR-T, as well as other adverse events, to determine which patients may be at greatest risk for these complications and how to modify these risks15.
Other Targets for CAR-T
In the wake of CAR-T’s efficacy results, the number of new studies has exploded, with over 150 clinical trials currently underway. These include investigations of CAR-T in other blood cancers, such as chronic lymphocytic leukemia (CLL) and multiple myeloma, a cancer formed by malignant plasma cells found in the bone marrow. Results from one early-stage trial in of CAR cell therapy in multiple myeloma has shown remission rates of 94% within 2 months of receiving therapy10. In November 2017, the FDA granted a breakthrough therapy designation for this therapy, based on the preliminary clinical data from this study16.
Research is also being conducted to explore CAR-T in the treatment of solid tumors, such as breast and colorectal cancer.
Based on current manufacturer pricing, CAR-T cell therapies cost from $373,000 to 475,000, which does not include the total costs of treatment, including follow-up care, or any intensive outpatient or hospital-related costs due to side effects17. It’s estimated that the total costs can be more than $1,000,000 per patient12, 17. Put into perspective, however, the cost of a stem cell transplant as a treatment of last resort in pediatric and young adults with ALL, can cost between $500,000 to $800,000 for the first year, with ongoing expenses thereafter12.
Several payment models for covering the costs of CAR-T treatment have been put forward, including reimbursement based on clinical outcomes, bundled payments for the total cost of the inpatient stay, and coverage for only hospitals and cancer centers, not small group practices, due to the potential for acute reactions17. As commercial and government payers consider coverage options, and more cell therapies are approved, the value and cost-effectiveness of high-priced CAR cell therapies that carry the promise of long-term survival and possible cures, will undoubtedly be a topic of intense discussion among stakeholders within the oncology community, as well as the broader healthcare ecosystem.
- Advance of the Year. American Society of Clinical Oncology. https://www.asco.org/research-progress/reports-studies/clinical-cancer-advances-2018/advance-year. Accessed April 2, 2018.
- FDA approval brings first gene therapy to the United States. U.S. Food and Drug Administration. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm. Accessed April 2, 2018.
- The Promise and Challenges of CAR-T Gene Therapy. Journal of the American Medical Association. https://jamanetwork.com/journals/jama/article-abstract/2664338?redirect=true. Accessed April 2, 2018.
- Adoptive Cellular Therapy (ACT) for Cancer Treatment. Progress in Cancer Immunotherapy. Advances in Experimental Medicine and Biology, vol 909. https://www.springer.com/us/book/9789401775533. Accessed April 2, 2018.
- Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version. National Cancer Institute. https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq. Accessed April 2, 2018.
- CAR T-Cell Therapy Approval Starts New Path in Childhood Leukemia. OncLive. http://www.onclive.com/web-exclusives/car-tcell-therapy-approval-starts-new-path-in-childhood-leukemia. Accessed April 2, 2018.
- Global Registration Trial of Efficacy and Safety of CTL019 in Pediatric and Young Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia: Update to the Interim Analysis. European Hematology Association Annual Congress. http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(17)31036-4/abstract. Accessed April 2, 2018.
- Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. New England Journal of Medicine. http://www.nejm.org/doi/full/10.1056/NEJMoa1709866. Accessed April 2, 2018.
- Tisagenlecleucel Responses in Pediatric ALL Sustained With Longer Follow-up. OncLive. http://www.onclive.com/web-exclusives/tisagenlecleucel-responses-in-pediatric-all-sustained-with-longer-followup. Accessed April 2, 2018.
- Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. New England Journal of Medicine. https://www.ncbi.nlm.nih.gov/pubmed/29226797. Accessed April 2, 2018.
- CAR T-Cell therapy can lead to long-lasting remissions in patients with lymphoma. National Cancer Institute Center for Cancer Research. https://ccr.cancer.gov/news/article/car-t-cell-therapy-can-lead-to-long-lasting-remissions-in-patients-with-lymphoma. Accessed April 2, 2018.
- How Durable Are CAR T-Cell Therapies? OncLive. http://www.onclive.com/publications/oncology-live/2018/vol-19-no-5/how-durable-are-car-tcell-therapies?p=4. Accessed April 2, 2018.
- Chimeric Antigen Receptor T-Cell Therapy. Leukemia & Lymphoma Society. http://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy. Accessed April 2, 2018.
- CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells. Accessed April 2, 2018.
- Biomarkers of Cytokine Release Syndrome and Neurotoxicity Related To CAR-T Cell Therapy. Biomarker Research. BMC. https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-018-0116-0. Accessed April 2, 2018.
- Celgene Corporation and bluebird bio Announce bb2121 Anti-BCMA CAR-T Cell Therapy Has Been Granted Breakthrough Therapy Designation from FDA and Prime Eligibility from EMA for Relapsed and Refractory Multiple Myeloma. Business Wire/Celgene Press Release. https://www.businesswire.com/news/home/20171116005818/en/Celgene-Corporation-bluebird-bio-Announce-bb2121-Anti-BCMA. Accessed April 2, 2018.
- Two Ways to Take Charge of CAR T-Cell Therapy Costs. Managed Healthcare Executive. http://managedhealthcareexecutive.modernmedicine.com/managed-healthcare-executive/news/two-ways-take-charge-car-t-cell-therapy-costs. Accessed April 2, 2018.