General AML

Treatment of CD33-Directed Chimeric Antigen Receptor-Modified T-Cells in One Patient with Relapsed and Refractory Acute Myeloid Leukemia

Consequently, researchers have investigated the use of Chimeric Antigen Receptor-Modified (CAR) T-cell therapy as a possible immunotherapeutic mode of destroying leukemic cells. There have been investigational studies where CD33-directed CAR T-cell (CART-33) therapy has demonstrated antileukemic effects, however the tolerability of this therapy has generated some apprehension regarding its clinical potential. In this clinical trial, Q.S. Wang et al. of the Chinese PLA General Hospital analyzed the effects of CART-33 in a 41 year old male patient with refractory AML.

This clinical trial was registered at www.clinicaltrials.gov under the registration number NCT01864902. The results were published in Molecular Therapy in August 2015.

The key findings were:
With regards to efficacy
  • CART-33 cells displayed cytolytic activity in primary AML blast cells with CD33 expression.
  • There was a >50% decrease in the blast ratio 2 weeks after the CART-33 infusion compared to prior treatment.
  • However, at 3, 5 and 9 weeks post-infusion the blast ratio increased to 22, 27 and nearly 70% respectively.
  • At 13 weeks post-infusion, the patient died as the leukemia continued to develop.
With regards to tolerability
  • The patient experienced transient high fever 0.5–1 hour after each daily cell infusion (the maximum temperature was 42°C).
  • A fluctuation in pre-existing pancytopenia was observed, although inversely related to the fever.
  • The patient, on two occasions, experienced reductions in their complete blood count after infusions of escalated CART doses.
  • The patient did not experience any detectable infections.
  • For a duration of 2 months, elevated serum levels of IL-6, TNF-α and INF-γ were observed.
Conclusion

Although this trial took place in only one patient (more patients are being currently recruited), the results have provided some useful data regarding the safety and efficacy of CAR T-cell therapy. In terms of efficacy, there were some initial benefits observed within the first two weeks post-infusion. Unfortunately, the patient’s disease still progressed resulting in death 13 weeks after CART-33 infusions. Regarding the safety concerns, CAR T-cell therapy like chemotherapy has resulted in myelosuppression. In this report, the patient’s blood cell counts were adversely affected, however this did not result in infection.

With respect to the potential role of this novel therapy in AML management, the authors made the following recommendation “CART-33 infusions serve as a short-term problem-resolving approach that may be more suitable as a debulking and/or immune hit strategy for the treatment of relapsed and refractory AML patients and that this approach should be followed by an intensive chemotherapy regimen or hematopoietic stem cell transplantation.”

Abstract

We conducted a clinical trial to assess the feasibility and efficacy of CD33-directed chimeric antigen receptor-modified T cells (CART-33) for the treatment of refractory acute myeloid leukemia (AML). A 41-year-old male patient with AML was enrolled and received a total of 1.12 × 109 autologous CART-33 cells, of which ~38% were transduced with CAR. The CART-33 infusion alone induced rigorous chills and fevers; drastic fluctuations of his pre-existing pancytopenia; elevated serum cytokine levels, including interleukin (IL)-6, IL-8, tumor necrosis factor-α, and interferon-γ; slight transient hyperbilirubinemia within 2 weeks; a subsequent intermittent moderate fever; and reversed fluctuation of the pancytopenia. A marked decrease of blasts in the bone marrow was observed on examination 2 weeks after therapy, and there was a gradual increase until florid disease progression occurred at 9 weeks after the cell infusion. These observations warrant further research on CART-33 treatment in refractory AML and may spur efforts to extend the CART-33-induced tumor burden to the preparation of other intensive strategies, such as hematopoietic stem cell transplantation. This study is registered at www.ClinicalTrials.gov as NCT01864902.

References
  1. Wang Q.S. et al. Treatment of CD33-directed Chimeric Antigen Receptor-modified T Cells in One Patient with Relapsed and Refractory Acute Myeloid Leukemia. Molecular Therapy 2015; 23(1):184–191. DOI:10.1038/mt.2014.164.