CAR T-Cell Therapy: A Healthcare Professional's Guide - KTE-C19 for Acute Lymphoblastic Leukemia
What is CAR T-Cell Therapy?
Chimeric antigen receptor (CAR) T-cell therapy is a newly approved cell therapy, the latest targeted, very personalized treatment engineered to actively seek out and destroy cancer. Recently, an FDA Advisory Committee gave their stamp of approval on this marvel of biomedical engineering. The FDA made a final approval for Kymriah (tisagenlecleucel) from Novartis on August 30, 2017 for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).
CAR T-cell therapy is not a "drug" in the usual sense; it is considered gene therapy, some call it a "living" drug. In CAR T, a patient's T cells (white blood cells) are separated out and engineered to express a chimeric antigen receptor (CAR) to target the tumor antigen. The tumor antigen, such as C19, is a protein on the surface of B-cell lymphomas and leukemias.
The re-engineered CAR T-cell is then infused back into the patient and redirects the T cell CAR receptor to find the cancer antigen and kill the cancer cell. It sounds like science fiction, but the National Cancer Institute, pharmaceutical industry, and major research universities are all involved.
For a brief introductory review of the tumor and CAR T-cell action, see these related slideshows:
CAR T-Cell FDA Approval: Status Update
Clinical trial results with Axi-Cel have been remarkable in refractory leukemias and lymphomas, leading to sustained, high rates of remission in a large percentage of treated patients.
However, treatments are not without serious risks and the manufacturing process is complicated and lengthy. Side effects, which can be difficult for the patient, can be managed by physicians in most cases. But it's important to remember when thinking about risks - these patients usually have limited or no other treatment options.
What is KTE-C19?
Axicabtagene ciloleucel (KTE-C19 or Axi-Cel) from Kite Pharma, and initially developed at the National Cancer Institute (NCI), is an anti-CD19 CAR-T therapy. KTE-C19 is under study for various relapsed and refractory hematologic malignancies, including:
- Aggressive B-cell non-Hodgkin lymphoma (diffuse large b-cell lymphoma, primary mediastinal b-cell lymphoma, and transformed follicular lymphoma) (ZUMA-1 trial) - this pivotal clincial trial is currently at the FDA undergoing regulatory review for approval for NHL.
- Relapsed/Refractory Mantle Cell Lymphoma (ZUMA-2 trial)
- Chronic Lymphocytic Leukemia (ZUMA-8 trial)
- Adult and Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia (ZUMA-3 and ZUMA-4 trials)
Axicabtagene Ciloleucel (KTE-C19): At the FDA
Aggressive B-cell non-Hodgkin lymphoma (NHL) is a malignancy with promising, advanced CAR T research. Axicabtagene ciloleucel (Axi-Cel, for short) is currently under priority FDA review for aggressive NHL with data from the ZUMA-1 trial.
On March 31, 2017, Kite announced they had completed the axicabtagene ciloleucel rolling submission for the Biologics License Application (BLA) for aggressive NHL, with an expected FDA approval decision date (PDUFA) by November 29th, 2017. If FDA-approved, Kite plans to launch axicabtagene ciloleucel in 2017, and it would be among the first commercially available CAR T cell therapies. The European Union submission of axicabtagene ciloleucel is expected in the 3rd quarter of 2017.
Use of KTE-C19 in Acute Lymphoblastic Leukemia
In addition to the priority review by the FDA for axicabtagene ciloleucel (KTE-C19) for refractory aggressive NHL, axi-cel is also under late Phase 1 research for treatment of refractory or relapsed acute lymphoblastic leukemia (r/r ALL).
ALL is a blood and bone marrow cancer that results in a multiplication of immature lymphocytes that are ineffective in fighting infections. Lymphoblasts crowd the bone marrow and prevent normal blood cells from forming. Healthy red blood cells from the bone marrow cannot be formed, leading to anemia.
There are several approaches to treatment of ALL:
- Blood transfusions
- Chemotherapy, targeted cancer therapy
- Radiation treatment
- Stem cell transplant
In patients who are refractory to these standard treatments or relapse after receiving them, CAR T-cell therapy may offer a last-chance hope for successful treatment.
ZUMA-3 and ZUMA-4 Trials
Non-Hodgkin lymphoma is furthest along in Kite's research pipeline, and is first to the FDA. In addition, KTE-C19 has shown impressive early results in difficult-to-treat patients with ALL. As reported in December 2016, in Phase 1 of the ZUMA-3 and ZUMA-4 trials, 13 patients with r/r ALL were treated with KTE-C19. In ZUMA-3, adults 18 years and older are being evaluated, and in ZUMA-4 pediatric and adolescent patients (ages 2 to 21) are being enrolled.
Preliminary analysis found:
- 9 of 11 patients (82%) achieved a complete remission or a complete remission with incomplete or partial blood count recovery.
- All responders (100%) tested negative for minimal residual disease (MRD), meaning low or no cancer cells in circulation, and is correlated with risk of disease relapse in ALL.
- Manufacturing of KTE-C19 was successful in all 13 patients in a period of 6 to 8 days.
Adverse events of grade 3 or higher included:
- Cytokine release syndrome (5 of 13 patients, 38%)
- Neurological events (5 of 13 patients, 38%), which can include events like aphasia, tremor, and seizures.
Two patients died: one in ZUMA-3 from KTE-C19-related cytokine release syndrome (CRS) and one in ZUMA-4 from an unrelated fungal infection. Larger Phase 2 studies in r/r ALL will be ongoing in 2017.
ZUMA-3 Update in Adults
In June 2017 an update to the ZUMA-3 trial in adults with r/r ALL was released. In the Phase 1 trial, 11 patients were treated with KTE-C19 at different target doses.
Reported results included:
- 73% of patients achieved complete remission, including those with incomplete or partial recovery of bone marrow.
- Ongoing complete remissions have been observed from 2 months to greater than 7.4 months.
- No dose-limiting toxicities occurred in the trial.
- KTE-C19 was successfully manufactured in 6 days. Vein-to-vein time has been reduced to about 17 days. The manufacturer reports this can be further improved by 2 or 3 days.
The company noted that once cell doses are optimized, pivotal Phase 2 research would commence in 2017.
Safety Update in ZUMA-3 for r/r ALL
In the adult population with r/r ALL in ZUMA-3, the safety data included:
- Grade 3 or higher cytokine release syndrome (CRS) occurred in 3 of 11 patients (27%)
- Grade 3 or higher neurologic events occurred in 6 of 11 patients (55%)
- Both of these adverse events were generally reversible.
As previously reported, one patient developed fatal CRS. In order to further improve the safety profile of KTE-C19, ZUMA-3 is also evaluating additional patients who will receive:
- Tocilizumab (Actemra), an interleukin-6 (IL-6) blocker, within 36 hours post-KTE-C19 infusion
- A lower dose of cell therapy.
On August 30, 2017 the FDA approved the use of Actemra for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS) in patients two years of age and older.
Finished: CAR T-Cell Therapy: A Healthcare Professional's Guide - KTE-C19 for Acute Lymphoblastic Leukemia
- 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
- Shah B, Castro J, Gokbuget N, et al. ZUMA-3: A phase 1/2 multi-center study evaluation the safety and efficacy of KTE-C19 anti-CD19 CAR T cells in adult patients with relapsed/refractory B precursor acute lymphoblastic leukemia (R/R ALL). Ann Oncol (2016) 27 (suppl_6): 415TiP. Accessed July 12, 2017 at https://academic.oup.com/annonc/article-abstract/27/suppl_6/415TiP/2799154/ZUMA-3-A-phase-1-2-multi-center-study-evaluation
- Kite Reports 73 Percent of Patients Achieved MRD Negative Complete Remission in Updated Analysis From Phase 1 ZUMA-3 CAR-T Trial of KTE-C19 in Adult Patients With High Burden Relapsed/Refractory Acute Lymphoblastic Leukemia. Press Release. Kite Pharma. June 5, 2017. Drugs.com. Accessed July 12, 2017 at https://www.drugs.com/clinical_trials/kite-reports-73-percent-patients-achieved-mrd-negative-complete-remission-updated-analysis-phase-1-17535.html
- Kite Pharma Reports 82 Percent of Patients Achieved Complete Remission in Preliminary Analysis from Phase 1 ZUMA-3 and ZUMA-4 Trials of KTE-C19 in Adult and Pediatric Patients with High Burden Relapsed/Refractory Acute Lymphoblastic Leukemia. Press Release. Kite Pharma. December 5, 2016. Drugs.com. Accessed July 13, 2017 at https://www.drugs.com/clinical_trials/kite-pharma-reports-82-percent-patients-achieved-complete-remission-preliminary-analysis-phase-1-17393.html
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- Leukemia and Lymphoma Society. Chimeric Antigen Receptor (CAR) T-Cell Therapy Fact Sheet. No. 27. Accessed July 12, 2017 at https://www.lls.org/sites/default/files/National/USA/Pdf/Publications/FS27_CAR_T-Cell_FS_4_17_FINAL.pdf
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- Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory aggressive diffuse large B-cell lymphoma (DLBCL): results from the international SCHOLAR-1 study. Presented at: the 2016 American Society of Clinical Oncology Annual Meeting; Chicago, Illinois; June 3-7, 2016. Abstract 7516.