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Personalized T-cell therapy yields promising outcomes in relapsed, refractory CLL
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Chimeric antigen receptor T-cell therapy produced durable responses in patients with relapsed and refractory chronic lymphocytic leukemia, according to the results of a pilot trial.
CLL continues to be incurable with traditional therapeutic approaches, and patients with multiply relapsed or refractory disease face poor outcomes.
Thus, David L. Porter, MD, Jodi Fisher Horowitz professor in leukemia care excellence and director of blood and marrow transplantation at University of Pennsylvania’s Abramson Cancer Center, and colleagues sought to determine whether chimeric antigen receptor (CAR)-modified T cells targeting the CD19 protein found on the surface of B cells could improve the low complete response rates by producing sustained remission in patients with relapsed and refractory CLL.
The researchers infused 14 patients (median age, 66 years; 85% men) with autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector at doses of 0.14 x 108 to 11 x 108 CTL019 cells (median, 1.6 x 108 cells). They monitored patients for toxicity, response, expansion and persistence of circulating CTL019 T cells.
The overall response rate was 57% (n = 8), with complete remission in four patients and partial remission in four patients.
The researchers observed that in vivo expansion of CAR T cells corresponded with clinical responses. In the first two patients in complete remission, CAR T cells persisted and remained functional for more than 4 years.
No patient in complete remission had relapsed at time of reporting. However, one patient in complete remission died. Three patients in partial remission died; the remaining patient experienced disease progression 13 months after treatment but remained alive at 36 months.
All patients who responded to therapy developed B-cell aplasia and experienced cytokine relapse syndrome, which coincided with T-cell proliferation.
The researchers did not detect minimal residual disease among patients in complete remission, which suggests that disease eradication may be attainable in some patients with relapsed or refractory disease.
Among the remaining patients who did not respond to therapy (n = 6), disease progression occurred 1 to 9 months after infusion. Two patients died, and the remaining four patients received other treatment options.
“The durability of the remissions we observed in this study are remarkable and have given us great hope that personalized cell therapies are going to be important options for patients whose cancers are no longer treatable with standard approaches,” Porter said in a press release. “The patients in this study are pioneers, whose participation has given us a foundation of knowledge and experience on which to build this new approach to help more patients.” – by Cameron Kelsall
Reference:
Porter DL, et al. Sci Transl Med. 2015;doi:10.1126/scitranslmed.aac5415.
Disclosure: Novartis provided funding for this study. Porter and four other study researchers report inventing the licensed technologies involved in the conduct of the trial, the patents for which are held by Novartis. The researchers and their institutions report receiving or being entitled to compensation benefits through this licensing relationship.
Perspective
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Dan S. Kaufman, MD, PhD
Two recent reports proved a key progress report on the CTL019 cell therapy product.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.
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