CAR T-Cell Therapy: A Healthcare Professional's Guide - Adverse Events
What is CAR T Cell Therapy?
Chimeric antigen receptor (CAR) T-cell therapy is a form of investigational targeted immunotherapy which could become the first gene therapy in the U.S. if the FDA deems approvable. CAR T-cell therapy is under study in patients with relapsed and refractory malignancies; lymphomas and leukemias are the furthest along in research. Typically, these patients have run out of standard options for cancer treatment, which include surgery, radiation, chemotherapy, or bone marrow transplant.
CAR T-cell therapy works with the patient's own immune system to help boost the cancer-killing effects of the T lymphocyte (T-cell), a white blood cell. In one form of CAR T, a patient's T cells are separated out and engineered to express a chimeric antigen receptor (CAR) to target the tumor antigen CD19, a protein expressed on the surface of most B-cell lymphomas and leukemias. The re-engineered CAR T-cell is then re-infused back into the patient and redirects the T cells to kill the cancer. But CAR T-cell therapy is not for the faint-of-heart; side effects can be daunting and dangerous.
For an introductory review of tumor pathophysiology and CAR T-cell mechanism of action, see these related slideshows:
Overview: Side Effects from CAR T-Cell Therapy
CAR T-cell therapy is a potent investigational treatment used in patients with high tumor burden. A positive response to CAR T-cell therapy leads to difficult, but often reversible, side effects of CAR T. Release of cytokines brought on by the infusion of the CAR T-cell therapy leads to many of these unique adverse reactions.
As studies continue in lymphomas, leukemias, and solid tumors, clinicians are learning how to manage these side effects, but fatalities have occurred. What are the expected adverse reactions to CAR T-cell therapy, and how are medical teams handling them?
The most commonly reported adverse effects seen in CAR T-cell therapy clincial trials include:
- Cytokine Release Syndrome (CRS)
- B-Cell Aplasia
- Tumor-Lysis Syndrome
- Cerebral Edema
Cytokine Release Syndrome (CRS)
Cytokine Release Syndrome (CRS) is one of the most common, but worrisome, serious side effects of CAR T-cell therapy. How does it occur? After engineering, the CAR T-cells are reinfused back into the patient which leads to the release of cytokines (chemical messengers) like interleukin 6 (IL-6) and IL-15 into the bloodstream. The cytokines aid the CAR T-cells to begin tumor attack.
Due to cytokine release, very high fevers, sharp drops in blood pressure, tachycardia, and low oxygenation can occur, usually in the first week. Neurotoxicity such as delirium, confusion, and seizure may appear, as well. Patients with more extensive disease may experience more serious events. Ironically, CRS is an effect of T-cell activiation which denotes a positive repsonse to therapy. In the ZUMA-1 study of agressive B-cell non-Hodgkin lymphoma, CRS and neurotoxicity occurred in roughly 13% and 28% of patients, respectively.
CRS can be life-threatening, but is reversible in most patients. Administration of tocilizumab (Actmera), an agent that blocks IL-6, has been used to manage cases of CRS, and researchers state that it does not appear to interfere with the CAR T cells' activity or proliferation. Etanercept (Enbrel), which blocks tumor necrosis factor, has also been used.
Neurotoxicity, which can occur in tandem with cytokine release syndome (CRS), includes symptoms such as aphasia, tremor, and seizures. Other reported CNS events include ataxia and confusion. The mechanisms leading to the symptoms are poorly understood, but active research is ongoing to unravel the mediators and develop preventive treatments.
In the ZUMA-1 trial, Kite's FDA-submitted pivotal trial for axicabtagene ciloleucel (KTE-C19), grade 3 or higher neurological adverse events occurred in 28% of patients, and encephalopathy was noted in 21% of participants.
Somnolence, agitation, and delirium are other specific neurotoxic side effects reported to occur with CAR T-cell therapy.
Cerebral edema (brain swelling) is another very serious and sometimes fatal adverse event encountered with CAR T treatment.
Eight cerebral edema-related deaths have been reported to date. Reports of 5 deaths due to cerebral edema came from the now shelved JUNO JCAR015 - ROCKET study of adult ALL patients. Two deaths were from the JUNO JCAR014 trial. One death was reported in the Kite ZUMA-1 Phase 2 safety studies, but all axicabtagene ciloleucel (KTE-C19) studies will continue as planned, as reported on May 8th, 2017.
Axicabtagene ciloleucel was submitted for FDA approval in March 2017 as treatment for patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant (ASCT).
Cerebral Edema: More Research Ongoing
Urgent questions that need to be answered now are:
- What are the mechanisms of severe neurotoxicity and cerebral edema?
- How can these serious, sometimes fatal side effects be avoided or managed?
Previously, it was suggested the chemotherapy drug fludarabine, part of a pre-conditioning treatment given to patients before CAR T-cell infusions, was to blame. Some manufacturers removed fludarabine from their pre-conditioning treatments, but others are still using it. This explanation was proven wrong when fludarabine was removed from preconditioning regimens, and there were still patient deaths.
However, severe neurological symptoms can occur with fludarabine treatment, even in the absence of CAR T-cell therapy. Cytokine release syndrome (CRS) can also result in severe neurotoxicity. In addition, many patients that develop serious side effects such as cerebral edema are already high-risk patients with an extremely high tumor burden; they are at the end of their treatment options. The culprit of cerebral edema involving CAR T-cell therapy is not fully known, but regulators are keeping a close eye on it. Using tolicizumab (Actemra) earlier to head off CRS and researching ways to "turn off" CAR T-cell therapy when needed are under research to address safety concerns.
B Cell Aplasia
One of the advantages of CAR T-cell therapy that targets the C19 tumor antigen is that C19 is not found on other cells except B cells, sparing other healthy tissues.
B cell aplasia occurs due to "on target-off tumor" toxicity, where the CAR T-cells destroy normal B cells. B cell aplasia is defined as low or absent B cells and is an expected side effect of CAR T. Depletion of B cells is near universal in patients treated with CAR T-cell therapy. Due to B cell depeletion, antibodies are not produced as readily and can lead to an elevated infection risk. B cell aplasia is managed with monthly intravenous immunoglobulin (Ig) infusions.
CAR T-cells can persist in a patient after infusion, and this effect can augment prolonged remissions, but also lead to prolonged B cell depletion. It is not not known if B cell aplasia will be an ongoing or reversible effect over time. Researchers are still learning about the length of B cell aplasia due to CAR T, reported to last from months to years.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is another known and expected side effect of CAR T-cell therapy. TLS occurs due to cell death and subsequent release of content into the bloodstream. Multiple metabolic and electrolyte complications ensue. Hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia may occur. Complications such as renal insufficiency, cardiac arrhythmias, seizures, and death due to multiorgan failure are possible.
The onset can begin one month or more after CAR T-cell treatment, and is a common complication in hematologic cancers. It's effects can be life-threatening. Treatment is typically standard supportive therapy.
ZUMA -1: Other Adverse Events
- Anemia (43%), thrombocytopenia (24%)
- Neutropenia (39%), febrile neutropenia (31%), decreased neutrophil count (32%)
- Decreased WBC count (29%), decreased lymphocyte count (20%)
- Cytokine release syndrome, CRS (13%)
Three deaths were reported; 2 deemed related to therapy. One case was reported as hemophagocytic lymphohistiocytosis, where the immune system damages the patient’s own tissues and organs, and one cardiac arrest in the setting of CRS.
In addition, in May 2017 a death due to cerebral edema in a Phase 2 portion of ZUMA-1 was also reported. The patient had explosive, refractory non-Hodgkin lymphoma. According to the company, this was the first grade 5 cerebral edema event recorded in approximately 300 patients treated with axicabtagene ciloleucel. The sponsor noted that all axicabtagene ciloleucel (KTE-C19) development studies will continue as planned.
Finished: CAR T-Cell Therapy: A Healthcare Professional's Guide - Adverse Events
- CAR T-Cell Therapy: Engineering Patients’ Immune Cells to Treat Their Cancers. National Cancer Institute (NCI). Accessed May 10, 2017 at https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
- Alamasbak H, Aarvak T, Vemuri M, et al. CAR T Cell Therapy: A Game Changer in Cancer Treatment. J of Immunology Research. 2016: Article ID: 5474602. Accessed May 3, 2017 at https://www.hindawi.com/journals/jir/2016/5474602/
- Leukemia and Lymphoma Society. Chimeric Antigen Receptor (CAR) T-Cell Therapy Fact Sheet. No. 27. Accessed May 10, 2017 at https://www.lls.org/sites/default/files/National/USA/Pdf/Publications/FS27_CAR_T-Cell_FS_4_17_FINAL.pdf
- KTE-C19 Approval Status. FDA Status. Drugs.com. Accessed April 23, 2017 at https://www.drugs.com/history/kte-c19.html
- Sharpe M, Mount N. Genetically modified T cells in cancer therapy: opportunities and challenges. Disease Models and Mechanisms. 2015;337-50. Accessed May 10, 2017 at http://dmm.biologists.org/content/8/4/337
- Carroll J. Lethally severe neurotoxicity continues to haunt Juno’s CAR-T pipeline. Endpoint News. December 3, 2016. Accessed May 11 at https://endpts.com/lethally-severe-neurotoxicity-continues-to-haunt-junos-car-t-pipeline/
- Kwon D. What do the CAR-T Patient Deaths Mean for the Future of the Field? Labiotech.eu. Accessed May 12, 2017 at http://labiotech.eu/cart-patient-deaths-juno
- Neelapu S. An Interim Analysis of the ZUMA-1 Study of KTE-C19 in Refractory, Aggressive Non-Hodgkin Lymphoma. Clinical Advances in Hematology & Oncology. Vol. Volume 15, Issue 2, February 2017. Accessed April 22, 2017 at http://www.hematologyandoncology.net/index.php/archives/february-2017/an-interim-analysis-of-the-zuma-1-study-of-kte-c19-in-refractory-aggressive-non-hodgkin-lymphoma/
- Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T-cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285-95. Accessed April 23, 2017 at http://www.cell.com/molecular-therapy-family/molecular-therapy/references/S1525-0016(16)45375-X
- Harris J. OncLive. Kite Reports Cerebral Edema Death in ZUMA-1 CAR T-Cell Trial. May 8, 2017. Accessed May 11, 2017 at http://www.onclive.com/web-exclusives/kite-reports-cerebral-edema-death-in-zuma1-car-tcell-trial?p=1
- Carroll J. One of Kite Pharma’s CAR-T patients died from cerebral edema, triggering a safety alarm. Endpoint News. May 8, 2017. Accessed May 11 at https://endpts.com/one-of-kites-car-t-patients-died-from-cerebral-edema-triggering-a-safety-alarm/
- Bernaski R. Looking Ahead: What's New In CAR T-Cell Therapy for Hematologic Malignancies. Cure. March 24, 2017. Accessed May 2, 2017 at http://www.curetoday.com/articles/looking-ahead-whats-new-in-cart-cell-therapy-for-hematologic-malignancies#sthash.wc2O8TXw.dpuf
- Howard S, Jones D, Ching-Hon P. The Tumor Lysis Syndrome. N Engl J Med. 2011 May 12; 364(19): 1844–1854. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437249/