Adaptimmune's Novel Cancer Therapeutics Show Positive Clinical Trial Results
News Jul 21, 2015
This is the first published study of lentiviral vector mediated TCR gene expression in humans. Novel findings include encouraging clinical responses, prolonged duration of persistence of TCR engineered cells and continued expression of the TCR on the cell surface; which is a departure from previously published studies in TCR gene therapy. In addition, high levels of IL-6 were detected, without serious cytokine release syndrome, which is in contrast to the side effects observed with multiple antibody-based CD19 immunotherapeutics to date. Clinical response rates were higher than expected for the patient population enrolled, and evidence supporting the expected mechanism of action of the TCR engineered cells was found.
“We believe these are significant data for Adaptimmune and for the cancer gene therapy field,” commented Dr. Rafael Amado, Adaptimmune’s Chief Medical Officer. “The trial showed that autologous transduced cells can be safely administered to patients with advanced myeloma in the context of stem cell transplantation, and that the transduced cells persist for a prolonged period of time. There was also encouraging evidence of antitumor effect which supports further investigation of cell and gene therapy in myeloma.”
The publication describes results of a Phase I/II trial to evaluate the safety and activity of autologous T-cells engineered to express an affinity-enhanced T-cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. All enrolled patients had symptomatic myeloma with active disease, representing an advanced stage population. Five patients (25 percent) had prior autologous stem cell transplant (ASCT) and 12 (60 percent) with cytogenetic abnormalities, including seven categorized as high-risk. After autologous stem cell collection, patients were conditioned with high-dose melphalan followed two days later by autologous stem cell infusion (ASCT). Patients received ADAP NY-ESO TCR (an average of 2.4 billion NY-ESOc259-engineered CD3 T-cells) two days after ASCT.
Encouraging clinical responses were observed in 16 patients (80 percent) in the study: Of the 20 patients, 14 patients (70 percent) had a near complete response or complete response, and another two had a very good partial response (VGPR) by three months post treatment. According to the authors, this compares favorably to the expected response frequencies following ASCT or double sequential (tandem) ASCT where response rates are typically less than 40 percent in patients without high risk disease.
Persistence of gene modified cells in the patients was prolonged. In this study, 19/20 patients continued to have gene marked cells detectable in blood at six months post infusion, and long term persistence of engineered cells in the peripheral blood was detectable in 90 percent of patients who reached two years follow up. Continued TCR expression was detected at two years, which suggested gene silencing was not occurring. Engineered T-cells also trafficked to sites of tumor; a majority of patients (15/20) underwent marrow biopsy for response assessment at day 100; 14/15 had detectable engineered cells. Previous studies with engineered T-cells (Burns et al., 2009; Robbins et al., 2014) reported no demonstrated persistence and expression beyond one month.
The method of T-cell manufacture may be key to enabling persistence; CD3/CD28 costimulation was used to manufacture cells in this study, and as well as in CAR studies for CD19 and HIV by the coauthors, and all of these studies demonstrate long term persistence of gene marked cells. This technology induces activation of the T-cell receptor through CD3 and simultaneous costimulation to the T-cells though the CD28 receptor. This selects for younger T-cells and also helps to program them for prolonged expansion. Adaptimmune holds an exclusive license from ThermoFisher (formerly Life Technologies Corporation) for methods of expanding and activating T-cells transduced with engineered T-cell receptors (TCR), including use of the ThermoFisher DynaBeads® CD3/CD28 technology.
Infusions were well-tolerated without clinically apparent cytokine release syndrome (CRS), or macrophage activation syndrome (MAS), despite high IL-6 levels. The observation of safety is a significant finding; CRS and MAS have been reported as significant safety concerns in multiple antibody-based CD19 immunotherapeutics to date. This differentiated safety profile may be related to physiological signaling and/or the antigen target and expression levels.
To evaluate antigen-specific anti-tumor activity of the engineered T-cells, RNA transcript levels in marrow specimens were quantitatively measured for NY-ESO-1 and LAGE-1, as well as CD138 as a measure of myeloma/plasma cell burden. Relative to levels at enrollment, loss of NY-ESO-1 and LAGE-1 transcripts was observed in 12/15 patients at day 100, and in 11/13 at day 180. At day 100, 3/15 patients had detectable levels of NY-ESO-1 and LAGE-1 transcripts. Notably, disease relapse was correlated with antigen escape (loss of NY-ESO and Lage expression in 2/10 cases) or loss of engineered T-cells (8/10 patients).
“These data suggest that treatment with enhanced NY-ESO-1/LAGE-1 TCR-engineered T-cells is not only safe but of potential clinical benefit to patients with certain types of aggressive multiple myeloma,” said Aaron P. Rapoport, MD, the Gary Jobson Professor in Medical Oncology at the University of Maryland School of Medicine and the Director of the Blood and Marrow Transplant Program at the University of Maryland Marlene and Stewart Greenebaum Cancer Center. “This study establishes a strong foundation for further research in cellular immunotherapy of myeloma. We hope to investigate additional combination approaches to boost the durability and function of the engineered T-cells to achieve even longer and deeper clinical responses.”
“This is the first report of TCR engineered T-cell therapy that has shown durable persistence in patients,” said Dr. Carl June, Richard W. Vague Professor in Immunotherapy, Department of Pathology and Laboratory Medicine, University of Pennsylvania. “These data are encouraging for the TCR platform, which I believe will be an important technology due to its ability to target intracellular antigens.”
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