CAR-T Cell Therapy - Advances in The Management of Multiple Myeloma
by Dr. C.H. Weaver M.D. updated 5/2020
CAR-T, or chimeric antigen receptor T-cells, is a new form of cancer immunotherapy in which a patient’s own T cells are removed and then engineered to identify and kill malignant multiple myeloma cells. The use of a patient’s own immune cells to fight cancer is proving to be a promising therapeutic approach in the treatment of some lymphomas and is now advancing in multiple myeloma.
One characteristic of a cancer cell is its ability to evade an attack by a person’s immune system. Immune cells are constantly surveying the body for potential threats, such as a bacteria or virus. Once the immune system detects such a threat, it initiates an attack against it.
One method of stimulating the immune system to detect cancer cells is referred to as chimeric antigen receptor T cell (CAR-T) therapy. Using this type of treatment, researchers take a sample of blood from the patient, and collect certain immune cells called T-cells.
Through laboratory processes, the collected T-cells are reprogrammed to recognize and attack the patient’s cancer cells. Once the T-cells multiply and reach a certain number in the laboratory (usually hundreds of millions to billions), they are re-infused into the patient. The infused T-cells then circulate throughout the body, attacking the patient’s cancer cells. (1-4)
Dr. James N. Kochenderfer, of the National Cancer Institute in Bethesda, Maryland, and colleagues reported results in the May 2019 New England Journal of Medicine on the feasibility of chimeric antigen receptor CAR T-cell therapy in individuals with multiple myeloma. The CAR T was bb2121, a B-cell maturation antigen (BCMA)-directed product. BCMA CAR T-cell Therapy-teaches T cells to recognize myeloma cells through a protein called B-cell maturation antigen (BCMA). There are several ongoing trials with BCMA as a target as well as other targets.
ASCO & American Society of Hematology CAR-T Update
The updated results from several clinical trials evaluating CAR-T cell therapies in development for the treatment of Multiple Myeloma were presented at the December 2019 American Society of Hematology Annual Meeting. Several conclusions can be drawn.
- CAR-T cell therapy is an evolving new treatment for Multiple Myeloma
- CAR-T cell therapy is effective in eradicating Myeloma in patients with refractory disease.
- A common side effect - Cytokine release syndrome (CRS) occurs in a majority of patients.
- Longer follow up is required to determine benefit in refractory patients.
JNJ-4528 CARTITUDE-1: Initial results from the early phase CARTITUDE-1 clinical trial evaluating JNJ-4528, an investigational B cell maturation antigen (BCMA)-directed CAR-T cell therapy for the treatment of patients with relapsed or refractory multiple myeloma were presented. The CARTITUDE- clinical trial is ongoing in patients with refractory multiple myeloma who have received at least three prior lines of therapy or are double refractory to a proteasome inhibitor and an immuomodulatory drug. (5)
JNJ-4528 is a novel CAR T-cell therapy featuring two molecules that bind to BCMA, a protein found on the surface of multiple myeloma cells. JNJ-4528 was evaluated in patients with multiple myeloma who had received a median of five prior therapies, and for whom standard-of-care treatments were no longer working.
CARTITUDE-1 clinical trial outcomes for the first 29 patients were updated in May 2020 at The American Society of Clinical Oncology Annual Meeting. Each patient had their T cells collected and sent to a laboratory where they were genetically engineered to express JNJ-4528. Prior to reinfusing these CAR-T cells, the patients received three days of chemotherapy to “make room” in their immune systems for the engineered T cells. Following chemotherapy, each patient received a single infusion of the JNJ-4528 CAR-T cells.
All patients responded to treatment, with an ORR of 100%. The stringent complete response (sCR) rate was 86%, 10% of patients had a very good partial response, and 3% had a partial response. The median time to complete response was 3 months. Overall 86% of patients remained alive and progression free approaching 12 months from treatment initiation.
The most common side effect reported was cytokine release syndrome (CRS) which occurred in a majority of patients. Neutropenia, anemia, and thrombocytopenia were also common. Two patient experienced severe CRS and one patient died of its complications. The onset of CRS was predictable generally occurring 2-12 days post-CAR-T cell infusion. In 76% of patients, CRS was treated with Actemra (tocilizumab).
The phase 2 portion of CARTITUDE-1 is fully enrolled and additional phase 2 and phase 3 studies have been initiated.
BM38 Dual-Targeted CAR T-Cell Therapy: More than 90% of patients with relapsed or refractory multiple myeloma responded to therapy with a bispecific CAR-T cell therapy that targets the CD38 protein and the B-cell maturation antigen (BCMA) found on myeloma cells, according to results of an early phase clinical trial. Sustained remissions also include nine patients with extramedullary multiple myeloma where disease has spread beyond the bone marrow. (6)
The bispecific CAR T-cell therapy was genetically engineered to target both the BCMA and CD38 proteins found on the surface of myeloma causing plasma cells. The clinical trial enrolled 22 patients with multiple myeloma that had returned or not responded to at least three therapies. Nine of the 22 patients had extramedullary disease.
Patients received three days of chemotherapy to “make room” in their immune systems for the engineered T cells. Then each patient was infused with the dual-targeted CAR-T cells. Patients were divided into five groups, with each group receiving a higher dose than the previous one. Depending on the cell dose, patients received either one or two infusions.
At a median follow up of 36 weeks 86% of patients had responded to treatment with 54.5% having no evidence of plasma cells detected in their bone marrow. In eight of the nine patients with extramedullary lesions their tumors were undetectable on their computed tomography scans. CAR-T cells in peripheral blood peaked from day 7 to day 15 after infusion among patients who had a serum complete response, and between days 14 and 30 for those who did not. BM38 CAR T cells were identified in the blood up to 450 days after infusion.
Twenty patients (91%) experienced CRS after the BM38 CAR T-cell infusion which is a well-documented side effect of CAR T cell therapy. Patients who developed CRS had their symptoms resolved with Actemra (tocilizumab) and supportive care. No other serious side effects were reported.
The investigators will continue to follow the patients for two years. They are also planning to conduct a phase II trial in both China and the United States to test the treatment’s effectiveness in a larger number of patients.
BM38 CAR T cells are the first dual-target CAR T cells that contain anti-BCMA and anti-CD38 in tandem for the treatment of multiple myeloma. Dual-target BM38 CAR T cells provide hope for patients with relapsed or refractory multiple myeloma with low expression of BCMA or single-target disease recurrence and extramedullary lesions.
KarMMa -Ide-cel: The KarMMa clinical trial evaluated Ide-cel CAR T cell therapy also targeting the BCMA protein expressed on the surface of normal and malignant plasma cells. The ide-cel CAR construct includes an anti-BCMA scFv-targeting domain for antigen specificity, a transmembrane domain, a CD3-zeta activation domain, and a 4-1BB co-stimulatory domain designed to increase T-cell activation, proliferation and persistence. Ide-cel CAR T cells are proposed to recognize and bind to BCMA on the surface of multiple myeloma cells leading to apoptosis.
The clinical trial has enrolled 140 patients, of whom 128 received ide-cel across the target dose levels of 150-450 x 106 CAR+ T cells after receiving lymphodepleting chemotherapy. All enrolled patients had received at least three prior treatment regimens and were refractory to their last regimen, defined as progression during or within 60 days of their last therapy.
At the target dose level 73% of patients overall responded to treatment for an average response duration of 10.6 months. CRS occurred in 83.6% of patients including one fatality and Neurotoxicity of any grade occurred in 18% of patients. (7)
Antibody-drug conjugate, GSK2857916
GSK2857916 combines an antibody that recognizes myeloma cells by attaching to the protein BCMA and the drug monomethyl auristatin F (MMAF), which kills the cells after they’re recognized. This is the first time this drug has been studied in humans, and the primary purpose of the study was to find a dose that is safe.
Second-generation CD38 antibody, MOR202
Darzalex, a CD38 antibody, has been shown to work well against myeloma. Early-phase investigations into a new antibody, MOR202, have preliminary results suggesting that the drug is effective against myeloma.
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- Maude S, Pulsipher M, Boyer M, et al. Efficacy and Safety of CTL019 in the First Phase II Multicenter Trial in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia: Results of an Interim Analysis. Proceedings from the 2016 annual meeting of the American Society of Hematology. Abstract #2801.
- Boldajipour B, Galetto R, Sommer C, et al. Preclinical Evaluation of Allogeneic Anti-BCMA Chimeric Antigen Receptor T Cells with Safety Switch Domains and Lymphodepletion Resistance for the Treatment of Multiple Myeloma. Proceedings from the 2016 annual meeting of the American Society of Hematology. Abstract #381.
- Raje N, et al "Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma" N Engl J Med 2019; 380:1726-1737.
- Xu J, Chen LJ, Yang SS, Sun Y, et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma [published online April 15, 2019]. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1819745116
- Long-term follow-up of a Phase 1, first-in-human open-label study of LCAR-B38M, a structurally differentiated CAR-T cell therapy targeting BCMA, in patients with RRMM. 2019 ASH Annual Meeting. December 2019.
- #930 A Bispecific CART-Cell Therapy Targeting BCMA and CD38 for Relapsed/Refractory Multiple Myeloma: Updated Results from a Phase I Dose-Climbing Trial.
- Bristol-Myers Squibb and bluebird bio Announce Positive Top-line Results from the Pivotal Phase 2 KarMMa Study of Ide-cel in Relapsed and Refractory Multiple Myeloma
- Cohen A, Popat R, Trudel S, et al. First in Human Study with GSK2857916, and Antibody Drug Conjugated to Microtubule-Disrupting Agent Directed Against B-Cell Maturation Antigen (BCMA) in Patients with Relapsed/Refractory Multiple Myeloma (MM): Results from Study BMA117159 Part 1 Dose Escalation. Proceedings from the 2016 annual meeting of the American Society of Hematology. Abstract #1148.
- Raab M, Chatterjee M, Goldschmidt H, et al. A Phase I/II Study of the CD38 Antibody MOR202 Alone and in Combination with Pomalidomide or Lenalidomide in Patients with Relapsed or Refractory Multiple Myeloma. Proceedings from the 2016 annual meeting of the American Society of Hematology. Abstract #1152.
- Berdeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. Presented at: ASCO20 Virtual Scientific Program. J Clin Oncol. 2020;38(suppl):abstr 8505.