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T-cell therapy leads to complete response in patient with refractory multiple myeloma
An infusion of autologous T cells transduced with an anti–CD19 chimeric antigen receptor led to a complete response in a patient with refractory multiple myeloma, according to a case report published in The New England Journal of Medicine.
The patient — a woman diagnosed with multiple myeloma in 2009 when aged 43 years — initially responded to treatment with lenalidomide (Revlimid, Celgene), bortezomib (Velcade; Takeda, Millennium) and dexamethasone, but experienced progression after a brief therapy cessation.
An autologous stem cell transplantation — followed by myeloablative chemotherapy with 200 mg/m2 melphalan — produced a brief partial response.
Alfred L. Garfall, MD, assistant professor of medicine at the Hospital of the University of Pennsylvania, and colleagues sought to determine whether autologous stem cell transplantation treatment with autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) could produce a complete response in the patient.
The patient underwent transplantation after receiving 140 mg/m2 melphalan. Transplant-related adverse events that the patient experienced included grade 4 neutropenia and thrombocytopenia, grade 3 mucositis, grade 2 nausea and anorexia, neutropenic fever and Staphylococcus aureus bacteremia.
The patient underwent CTL019 infusion 12 days after transplantation, at a dose of 5 x 107. The researchers observed no fevers or signs of cytokine release syndrome after infusion.
No adverse events related to CTL019 occurred. Further, all transplantation-related adverse events resolved by day 100 after the procedure.
The patient began a treatment regimen of 5 mg daily lenalidomide beginning day 130 after transplantation. The researchers subsequently reduced the dose to 5 mg twice weekly due to gastrointestinal adverse events.
The patient achieved a complete response — with no evidence of progression and no measurable serum or urine monoclonal protein at 12 months — despite the absence of CD19 expression in 99.95% of her neoplastic plasma cells.
“Ten patients, including the patient described in detail here, have been treated so far in this trial,” Garfall and colleagues wrote. “Six of the 10 patients remain progression-free. The only additional CTL019-attributable adverse events observed have been one instance of grade 1 cytokine release syndrome and one instance of grade 3 enterocolitis due to autologous graft-versus-host disease.” – by Cameron Kelsall
Disclosure: Novartis provided funding for this study. Garfall reports grants from Novartis and the NIH/NCI during the conduct of the study. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Use of autologous T cells transduced with chimeric antigen receptors (CAR) to mediate killing of refractory disease has received remarkable attention in the last couple of years, although the number of patients treated and follow-up on those patients has been relatively modest.
The report by Porter and colleagues gives more detailed information and longer follow-up of 14 patients with chronic lymphocytic leukemia who received CTL019. Most notably, four patients (29%) achieved complete remission (CR) with strong likelihood of complete eradication of their disease. It is clear that CR is mediated by long-term expansion and survival of these CTL019 cells. Patients receiving this therapy had differing lymphocyte-depleting conditioning regimens prior to CTL019 therapy and, unfortunately, there is no data provided whether differing conditioning regimens led to improved survival of the T-cell product.
Additionally there are no data provided whether other high-risk features such as TP53/17p deletion were associated with persistent disease, or whether high-risk disease could be eradicated by CTL019. It is also noted that several patients had cytokine release syndrome (CRS), and treatment by the anti-IL6 antibody tocilizumab (Actemra, Genentech) rapidly reversed this condition with no apparent adverse effect on the CTL product; however, one patient who received steroids for CRS lost the CTL product after that therapy. Also, as expected, patients in these studies treated with CTL019 had long-term B-cell aplasia, which emphasizes the continuing search for methodology to eliminate the CAR-transduced T cells if desired once CR and likely disease eradication has been achieved.
The case report by Garfall and colleagues demonstrates complete eradication of immunoglobulin A multiple myeloma after autologous hematopoietic cell transplant combined with CTL019. This apparent CR is remarkable, as only 0.05% of the myeloma cells expressed CD19. Further study is required to determine whether this is a progenitor/stem cell-type population that may give rise to the malignant CD19-plasma cell population. The supplemental data demonstrate that this case report highlights only one of 10 patients with multiple myeloma who received CTL019. Although six of the 10 treated patients achieved a CR, only one additional patient at the time of this report was greater than 100 days post treatment. CTL019 and other CAR-based therapies (for example, targeting NY-ESO-1) provide a promising avenue for treatment of multiple myeloma that becomes refractory to standard therapy. However, further study is needed to better define how CAR-based therapy compares with allogeneic hematopoietic cell transplant, which can provide a curative option for patients with refractory CLL, multiple myeloma and other hematologic malignancies.