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<p>Adoptive transfer of unselected autologous tumor-infiltrating lymphocytes (TILs) has mediated meaningful clinical responses in patients with metastatic melanoma but not in cancers of gastrointestinal epithelial origin. In an evolving single-arm phase 2 trial design, TILs were derived from and administered to 91 patients with treatment-refractory mismatch repair proficient metastatic gastrointestinal cancers in a schema with lymphodepleting chemotherapy and high-dose interleukin-2 (three cohorts of an ongoing trial). The primary endpoint of this study was the objective response rate as measured using Response Evaluation Criteria in Solid Tumors 1.0; safety was a descriptive secondary endpoint. In the pilot phase, no clinical responses were observed in 18 patients to bulk, unselected TILs; however, when TILs were screened and selected for neoantigen recognition (SEL-TIL), three responses were seen in 39 patients (7.7% (95% confidence interval (CI): 2.7–20.3)). Based on the high levels of programmed cell death protein 1 in the infused TILs, pembrolizumab was added to the regimen (SEL-TIL + P), and eight objective responses were seen in 34 patients (23.5% (95% CI: 12.4–40.0)). All patients experienced transient severe hematologic toxicities from chemotherapy. Seven (10%) patients required critical care support. Exploratory analyses for laboratory and clinical correlates of response were performed for the SEL-TIL and SEL-TIL + P treatment arms. Response was associated with recognition of an increased number of targeted neoantigens and an increased number of administered CD4<sup>+</sup> neoantigen-reactive TILs. The current strategy (SEL-TIL + P) exceeded the parameters of the trial design for patients with colorectal cancer, and an expansion phase is accruing. These results could potentially provide a cell-based treatment in a population not traditionally expected to respond to immunotherapy. ClinicalTrials.gov identifier: <a href="https://clinicaltrials.gov/study/NCT01174121">NCT01174121</a>.</p>

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Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial

  • 期刊论文

  • 发表日期：

    2025年4月1日

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  • Frank J. Lowery,
  • Stephanie L. Goff,
  • Billel Gasmi,
  • Maria R. Parkhurst,
  • Nivedita M. Ratnam,
  • Hyunmi K. Halas,
  • Thomas E. Shelton,
  • Michelle M. Langhan,
  • Aarushi Bhasin,
  • Aaron J. Dinerman,
  • Victoria Dulemba,
  • Ian S. Goldlust,
  • Alexandra M. Gustafson,
  • Abraham A. Hakim,
  • Kyle J. Hitscherich,
  • Lisa M. Kenney,
  • Lior Levy,
  • Juliette G. Rault-Wang,
  • Alakesh Bera,
  • Satyajit Ray,
  • Courtney D. Seavey,
  • Chuong D. Hoang,
  • Jonathan M. Hernandez,
  • Jared J. Gartner,
  • Sivasish Sindiri,
  • Todd D. Prickett,
  • Lori S. McIntyre,
  • Sri Krishna,
  • Paul F. Robbins,
  • Nicholas D. Klemen,
  • Mei Li M. Kwong,
  • James C. Yang,
  • Steven A. Rosenberg

摘要

Adoptive transfer of unselected autologous tumor-infiltrating lymphocytes (TILs) has mediated meaningful clinical responses in patients with metastatic melanoma but not in cancers of gastrointestinal epithelial origin. In an evolving single-arm phase 2 trial design, TILs were derived from and administered to 91 patients with treatment-refractory mismatch repair proficient metastatic gastrointestinal cancers in a schema with lymphodepleting chemotherapy and high-dose interleukin-2 (three cohorts of an ongoing trial). The primary endpoint of this study was the objective response rate as measured using Response Evaluation Criteria in Solid Tumors 1.0; safety was a descriptive secondary endpoint. In the pilot phase, no clinical responses were observed in 18 patients to bulk, unselected TILs; however, when TILs were screened and selected for neoantigen recognition (SEL-TIL), three responses were seen in 39 patients (7.7% (95% confidence interval (CI): 2.7–20.3)). Based on the high levels of programmed cell death protein 1 in the infused TILs, pembrolizumab was added to the regimen (SEL-TIL + P), and eight objective responses were seen in 34 patients (23.5% (95% CI: 12.4–40.0)). All patients experienced transient severe hematologic toxicities from chemotherapy. Seven (10%) patients required critical care support. Exploratory analyses for laboratory and clinical correlates of response were performed for the SEL-TIL and SEL-TIL + P treatment arms. Response was associated with recognition of an increased number of targeted neoantigens and an increased number of administered CD4+ neoantigen-reactive TILs. The current strategy (SEL-TIL + P) exceeded the parameters of the trial design for patients with colorectal cancer, and an expansion phase is accruing. These results could potentially provide a cell-based treatment in a population not traditionally expected to respond to immunotherapy. ClinicalTrials.gov identifier: NCT01174121.