CAR T - Scientific Advances in The Management of Multiple Myeloma

May 2019 update on CAR T in multiple myeloma and other targeted therapies. CAR T looks very promising.

by Dr. C.H. Weaver M.D. updated 5/3/2019

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.

CTL019 CAR T-cell Therapy-engineers a patient’s own T cells to teach them to recognize and attack myeloma cells. CTL019 is designed to attack myeloma stem cells, a cell type that can give rise to many more myeloma cells. A pilot study reported that this approach was safe and feasible a phase 2 trial evaluating this approach is ongoing.

BCMA CAR T-cell Therapy-teaches T cells to recognize myeloma cells through a protein called B-cell maturation antigen (BCMA). This approach was reported to have promise in treating myeloma in patients who had already failed other therapies. There are several ongoing trials with BCMA as a target.

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 a novel chimeric antigen receptor CAR T-cell therapy from a phase I clinical trial in heavily pretreated individuals with multiple myeloma. The CAR T was bb2121, a B-cell maturation antigen (BCMA)-directed product,

The phase I trial enrolled 36 patients with relapsed or refractory multiple myeloma at centers across the U.S. Eligible patients had to have been treated with a minimum of three previous lines of therapy, including an immunomodulatory agent and a proteasome inhibitor, but most were far more heavily pretreated having received an average of 7 - 8 prior therapies

The CAR T-cell therapy was successfully manufactured in all patients, but three experienced disease progression prior to the infusion and were unable to receive the bb2121 CAR T cell therapy. Of 33 patients treated 85% achieved an objective response. The median duration of response was 10.9 months and all responders evaluated for minimal residual disease had no identifiable myeloma.

Cytokine release syndrome occurred in 76% of patients but were mostly grade 1/2 (70%). Two grade 3 cases (the remaining 6%) resolved within 24 hours.(3)

A response rate of nearly 90% was achieved in another exploratory clinical study of CAR-T therapy using a CAR-T preparation called LCAR-B38M that is targeted against 2 distinct epitopes on BCMA.(4)

Of the 17 patients with refractory multiple myeloma treated with LCAR-B38M at 3 clinical centers in China between April 2017 and November 22, 2017 an overall response rate of 88.2% was achieved. Furthermore, 7 patients with complete remissions had ongoing responses at 11 months following CAR-T infusion.

Cytokine release syndrome (CRS) was experienced by all 17 patients in the study, with 6 patients experiencing grade 3 CRS, and 1 case of CRS-related death. All patients with severe CRS, and 3 with mild CRS (grade 1/2) required treatment with the anti-interleukin 6 receptor blocker, tocilizumab, with symptoms typically resolving within 7 days following administration.

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.

References:

  1. 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.
  2. 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.
  3. 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.
  4. 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
  5. 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.
  6. 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.

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