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

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

doi:10.1038/s41591-025-03627-5

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

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 RayCourtney 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^*

^*Corresponding author for this work

Anesthesiology

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1994-2003
Number of pages	10
Journal	Nature Medicine
Volume	31
Issue number	6
DOIs	https://doi.org/10.1038/s41591-025-03627-5
State	Published - Jun 2025

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Lowery, F. J., Goff, S. L., Gasmi, B., Parkhurst, M. R., Ratnam, N. M., Halas, H. K., Shelton, T. E., Langhan, M. M., Bhasin, A., Dinerman, A. J., Dulemba, V., Goldlust, I. S., Gustafson, A. M., Hakim, A. A., Hitscherich, K. J., Kenney, L. M., Levy, L., Rault-Wang, J. G., Bera, A., ... Rosenberg, S. A. (2025). Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial. Nature Medicine, 31(6), 1994-2003. https://doi.org/10.1038/s41591-025-03627-5

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title = "Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial",

abstract = "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.",

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

note = "Publisher Copyright: {\textcopyright} This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2025.",

year = "2025",

month = jun,

doi = "10.1038/s41591-025-03627-5",

language = "English",

volume = "31",

pages = "1994--2003",

journal = "Nature Medicine",

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Lowery, FJ, Goff, SL, Gasmi, B, Parkhurst, MR, Ratnam, NM, Halas, HK, Shelton, TE, Langhan, MM, Bhasin, A, Dinerman, AJ, Dulemba, V, Goldlust, IS, Gustafson, AM, Hakim, AA, Hitscherich, KJ, Kenney, LM, Levy, L, Rault-Wang, JG, Bera, A, Ray, S, Seavey, CD, Hoang, CD, Hernandez, JM, Gartner, JJ, Sindiri, S, Prickett, TD, McIntyre, LS, Krishna, S, Robbins, PF, Klemen, ND, Kwong, MLM, Yang, JC & Rosenberg, SA 2025, 'Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial', Nature Medicine, vol. 31, no. 6, pp. 1994-2003. https://doi.org/10.1038/s41591-025-03627-5

TY - JOUR

T1 - Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers

T2 - a phase 2 trial

AU - Lowery, Frank J.

AU - Goff, Stephanie L.

AU - Gasmi, Billel

AU - Parkhurst, Maria R.

AU - Ratnam, Nivedita M.

AU - Halas, Hyunmi K.

AU - Shelton, Thomas E.

AU - Langhan, Michelle M.

AU - Bhasin, Aarushi

AU - Dinerman, Aaron J.

AU - Dulemba, Victoria

AU - Goldlust, Ian S.

AU - Gustafson, Alexandra M.

AU - Hakim, Abraham A.

AU - Hitscherich, Kyle J.

AU - Kenney, Lisa M.

AU - Levy, Lior

AU - Rault-Wang, Juliette G.

AU - Bera, Alakesh

AU - Ray, Satyajit

AU - Seavey, Courtney D.

AU - Hoang, Chuong D.

AU - Hernandez, Jonathan M.

AU - Gartner, Jared J.

AU - Sindiri, Sivasish

AU - Prickett, Todd D.

AU - McIntyre, Lori S.

AU - Krishna, Sri

AU - Robbins, Paul F.

AU - Klemen, Nicholas D.

AU - Kwong, Mei Li M.

AU - Yang, James C.

AU - Rosenberg, Steven A.

PY - 2025/6

Y1 - 2025/6

N2 - 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.

AB - 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.

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