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Its T time
September 2015
by Lori Lesko  |  Email the author
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OXFORD, U.K.—Armed with its T cell weapon for battling cancer, biopharmaceutical company Adaptimmune Therapeutics has announced that in a Phase 1/2 study, its affinity enhanced T cell receptor (TCR) demonstrated durable persistence, clinical activity and tolerability in multiple myeloma patients. The study was published July 20 online and in the August 2015 print edition of Nature Medicine.
 
The paper, authored by Drs. Aaron P. Rapoport, Edward Stadtmauer and Gwendolyn Binder-Scholl and colleagues describes the persistence and tumor trafficking, antitumor effect and safety profile of Adaptimmune’s NY-ESO TCR therapeutic (ADAP NY-ESO TCR) in 20 patients with advanced multiple myeloma.
 
Adaptimmune has aimed to utilize the body’s own machinery—the T cell—to target and destroy cancerous tumors by using engineered, increased affinity T cell receptors (TCRs) as a means of strengthening natural patient T cell responses.
 
The Nature Medicine article is reportedly 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—a departure from previously published studies in TCR gene therapy. Clinical response rates were higher than expected for the 20 patients 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,” Dr. Rafael Amado, Adaptimmune’s chief medical officer, states. “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.”
 
Previous studies “used retroviral vectors to deliver the TCR gene,” Amado tells DDNews. “In this study, we used a lentiviral vector to introduce the TCR into T cells. The cells carrying the TCR expanded in patients, trafficked to the bone marrow, killed plasma cells (the cancer cell in multiple myeloma) and persisted for at least one year post-infusion.”
 
“We are very encouraged by these preliminary data,” Amado said. “We will consider these and other results from our program and decide on potential next steps.”
 
Adaptimmune’s main headquarters are in Oxford, England, where it has a research base, he said. The company’s clinical base is in Philadelphia and “we are currently running trials in multiple cancers across the U.S. The University of Maryland Greenebaum Cancer Center and Abramson Cancer Center of the University of Pennsylvania both participated in the study.”
 
“T cell receptors can be engineered to target any cancer antigen, and therefore, this technology potentially has great applicability across multiple cancer types,” Amado adds. “In the case of NY-ESO, it is expressed in multiple tumors including solid tumors like ovarian cancer, lung, melanoma and others. We have programs with other TCRs that address other tumor types.”
 
Despite recent therapeutic advances, multiple myeloma remains a treatable but incurable cancer. Patients are typically treated with repeat rounds of combination therapy with the time intervals to relapse becoming shorter with each successive line of therapy. The majority of patients eventually have a relapse which cannot be further treated.
 
All enrolled patients in the recently published study 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) had 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).
 
Encouraging clinical responses were observed in 16 patients (80 percent) in the study. Of the 20 patients, 14  (70 percent) had a near-complete or complete response, and another two had a very good partial response (VGPR) by three months post-treatment, the study states.
 
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, researchers reported. In this study, 19 of 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, the study states. Engineered T cells also trafficked to sites of tumors; a majority of patients (15 of 20) underwent marrow biopsy for response assessment at day 100, and 14 of those 15 had detectable engineered cells. Previous studies with engineered T cells reported no demonstrated persistence and expression beyond one month.
 
The method of T cell manufacture may be key to enabling persistence; CD3/CD28 co-stimulation was used to manufacture cells in this study, as well as in CAR studies for CD19 and HIV by the co-authors, and all of these studies demonstrated 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, researchers found. This selects for younger T cells and also helps to program them for prolonged expansion.
 
The study showed 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.
 
“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,” wrote the study authors.
 
“This study establishes a strong foundation for further research in cellular immunotherapy of myeloma,” says Rapoport. “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,” stated Dr. Carl June, Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine at the 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.”
 
Leerink Partners analysts Michael Schmidt and Jonathan Chang wrote that, “We believe recently announced collaborations in the T cell immunotherapy space bode well for Adaptimmune as they highlight the continued strong interest in the field of T cell-based immunotherapies, including TCR-based T cell therapy. We believe Adaptimmune’s TCR technology is differentiated from others, and we think the company is well positioned to capitalize on its platform.”
 
Compelling clinical data for the NY-ESO program provide strong proof of concept for Adaptimmune, the analysts maintain, adding that its lead program targeting NY-ESO-1 “has generated impressive responses in multiple myeloma and in synovial sarcoma, while toxicities have been manageable.”
 
Code: E091517

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