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Nonengineered T-cells May be ‘Clinically Meaningful’ for Pancreatic Cancer
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More than half of patients with pancreatic adenocarcinoma showed clinical responses when treated with an investigational multiantigen-specific T-cell therapy, according to the results of an ongoing phase 1 clinical trial presented at the ACCR’s Immune Cell Therapies for Cancer conference in San Francisco.
The nonengineered T-cell therapy used immune system cells called tumor-associated antigen (TAA)-specific cytotoxic T lymphocytes that simultaneously target the TAAs PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin.
“There is a dire need for better systemic therapies in all stages of pancreatic cancer, and there is a need for these systemic therapies to be better tolerated than the current standards of two to three chemotherapy drug combination regimens,” Brandon G. Smaglo, MD, FACP, an assistant professor of internal medicine and oncology at Baylor College of Medicine’s Dan L. Duncan Comprehensive Cancer Center and co-author of the study, told Cell Therapy Next.
“With the recent advances of immunotherapies in other cancer types, pursuing an immune therapy trial such as what we are conducting was attractive both from an efficacy and tolerability point of view.”
The study included three treatment arms in which researchers evaluated the safety and feasibility of multiTAA T cells as well as progression-free and overall survival. Arm A included patients with unresectable or metastatic pancreatic adenocarcinoma whose disease responded to standard first-line chemotherapy. Arm B comprised patients with progressive or refractory disease after first-line chemotherapy. Finally, Arm C included patients with potentially resectable disease.
The investigators generated 35 clinical-grade multiTAA T cell lines that included CD3+ T cells (mean 97.2 ± 1.3%) with a mix of CD4+ (mean 47.2 ± 7.4%) and CD8+ (mean 39.5 ± 6.4%) T cells that recognize the antigens PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin.
“Our approach is novel because, unlike a CAR T-cell approach, the T cells we are using are nonengineered. They are cultured in a mixture with the antigens we intend for them to target so that they can naturally acquire these features,” Smaglo said.
The cell manufacturing process takes 4 to 6 weeks, he added. Patients will receive six doses of the cells, which are all manufactured in a single run.
“It is important that potential patients be identified early, so that when the T cells are needed for use, they are ready,” Smaglo said.
Eighteen patients received treatment with multiTAA T cells (Arm A, n = 9; Arm B, n = 6; Arm C, n = 3). Each patient received up to 6 monthly infusions of 1 × 107 multiTAA T cells/m2.
Treatment Arm A included one patient with a complete response, two with disease progression, five with stable disease or ongoing response (range, 6-9 months) to therapy, and two who are too early to evaluate.
Arm B included patients with progressive disease. The study showed that three patients continued disease progression, while three other patients showed ongoing stable disease (range, 1-6 months).
Arm C included patients with potentially resectable disease; these patients received one preoperative infusion of T cells and are still receiving postoperative infusions and adjuvant therapy.
The investigators noted that the clinical benefit of multiTAA T-cell therapy correlated with the detection of tumor-reactive T cells in patients’ peripheral blood for all three treatment arms, and within postinfusion tumor biopsy samples in study Arm C.
“T cells have exhibited activity against targeted antigens as well as nontargeted TAAs, including MAGEA2B and AFP, indicating induction of antigen/epitope spreading,” Smaglo and colleagues wrote.
Study data showed that no patient treated with multiTAA T cells experienced infusion-related systemic toxicities or neurotoxicity. Immune-related toxicity and neurotoxicity are common adverse effects from autologous engineered cell therapies, such as CAR T-cell therapy.
“Because our product is autologous and not engineered, we expected little if any toxicity, and this has indeed been the case,” Smaglo told Cell Therapy Next. “No significant adverse events or toxicity attributable to the product have been observed,” he added.
This lack of treatment-related toxicities allowed the investigators to use a multiple dose strategy in this study, Smaglo noted.
“This approach is safe and feasible; there have been no side effects to speak of and patients tolerate the therapy without issue,” he said.
“There have been some exciting responses from individual patient tumors. ... The initial results suggest that further development of this technique is worthwhile and the risk to patients is minimal.”
When asked if the results of this study had a potential impact on clinical practice, Smaglo responded that although the results were promising, it was too early to answer the question.
“I am excited to complete this trial and to explore this technology further in additional studies,” he said.
“So far, the results certainly suggest a feasible, tolerable and probably clinically meaningful option.” – by Drew Amorosi
For more information:
Brandon G. Smaglo, MD, FACP, can be reached at Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, 7200 Cambridge St., 7B, Houston, TX 77030; email: smaglo@bcm.edu.
Reference:
Smaglo BG, et al. Abstract #PR01. Presented at: AACR’s Immune Cell Therapies for Cancer; July 19-22, 2019; San Francisco.
Disclosures: Smaglo reports speakers bureau role for Taiho Oncology. The other authors report no relevant financial disclosures.