Publications by authors named "Seth Wardell"
Article Synopsis
- Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) shows clinical efficacy in metastatic melanoma, with a 42% overall response rate across 74 patients.
- Prior treatment with anti-CTLA4 impacts TIL ACT outcomes negatively, leading to shorter survival and reduced response rates, particularly in patients who were pre-treated with this checkpoint inhibitor.
- Baseline serum IL9 levels may predict response to TIL ACT, suggesting a potential strategy for sequencing immunotherapies in treating melanoma patients.
Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion: The Advantage Over the Sole Use of Interleukin-2 in Cutaneous and Uveal Melanoma.
J Immunother
September 2019
Article Synopsis
- The study proposes a new approach to improve tumor-infiltrating lymphocyte (TIL) therapy by speeding up the expansion process through a combination of T-cell receptor activation and stimulation of specific markers (CD137/4-1BB and IL-2).
- This 3-signal method resulted in rapid and consistent growth of CD8 TIL from melanoma tumors, achieving successful expansion in all cultures tested in less than three weeks.
- The enhanced TILs showed the ability to recognize and target melanoma cells, presenting a significant advancement for the application of TIL therapy in difficult-to-treat cancers like uveal melanoma.
Following the clinical success achieved with the first generation of adoptive cell therapy (ACT) utilizing expanded tumor-infiltrating lymphocytes (TILs), the second and third generations of TIL ACT are evolving toward the use of genetically modified TIL. TIL therapy generally involves the transfer of a high number of TIL, ranging from 10 to 10 cells. One of the technical difficulties in genetically modifying TIL, using a retroviral vector, is the ability to achieve large expansion of transduced TIL, while keeping the technique suitable to a Good Manufacturing Practices (GMP) environment.
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- Patients with leptomeningeal disease (LMD) from melanoma typically have poor outcomes and limited treatment options.
- A case study highlights the use of intrathecal (i.t.) administration of autologous tumor-infiltrating lymphocytes (TIL) for a patient who had previously undergone multiple treatments but saw disease progression after i.t. IL2 therapy.
- The patient experienced disease stabilization with the i.t. TIL treatment and had no unexpected toxicities, suggesting that this method is safe and warrants further clinical trials to assess its potential benefits for LMD patients.
Purpose: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response.
Experimental Design: Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy.
Purpose: In this study, we assessed the specific role of BRAF(V600E) signaling in modulating the expression of immune regulatory genes in melanoma, in addition to analyzing downstream induction of immune suppression by primary human melanoma tumor-associated fibroblasts (TAF).
Experimental Design: Primary human melanocytes and melanoma cell lines were transduced to express WT or V600E forms of BRAF, followed by gene expression analysis. The BRAF(V600E) inhibitor vemurafenib was used to confirm targets in BRAF(V600E)-positive melanoma cell lines and in tumors from melanoma patients undergoing inhibitor treatment.
The E6 and E7 oncoproteins of the high-risk HPV type16 represent ideal targets for HPV vaccine development, they being consistently expressed in cervical cancer lesions. Since HPV-16 is primarily transmitted through genital mucosal route, mucosal immune responses constitute an essential feature for vaccination strategies against HPV-associated lesions. We present here evidence showing that mucosal immunization of mice by the intranasal route with a mixture of peptides E7(44-62) and E6(43-57) from the E7 and E6 oncoproteins of HPV-16, respectively, using a mutant cholera toxin adjuvant (CT-2*), primed strong antigen-specific cellular immune responses in systemic and mucosal tissues.
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