CD8+ enriched "Young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma

Mark E. Dudley, Colin A. Gross, Michelle M. Langhan, Marcos R. Garcia, Richard M. Sherry, James C. Yang, Giao Q. Phan, Udai S. Kammula, Marybeth S. Hughes, Deborah E. Citrin, Nicholas P. Restifo, John R. Wunderlich, Peter A. Prieto, Jenny J. Hong, Russell C. Langan, Daniel A. Zlott, Kathleen E. Morton, Donald E. White, Carolyn M. Laurencot, Steven A. Rosenberg

Research output: Contribution to journalArticle

Abstract

Purpose: Tumor-infiltrating lymphocytes (TIL) and interleukin (IL)-2 administered following lymphodepletion can cause the durable complete regression of bulky metastatic melanoma in patients refractory to approved treatments. However, the generation of a unique tumor-reactive TIL culture for each patient may be prohibitively difficult. We therefore investigated the clinical and immunologic impact of unscreened, CD8+ enriched "young" TIL. Experimental Design: Methods were developed for generating TIL that minimized the time in culture and eliminated the individualized tumor-reactivity screening step. Thirty-three patients were treated with these CD8+ enriched young TIL and IL-2 following nonmyeloablative lymphodepletion (NMA). Twenty-three additional patients were treated with CD8+ enriched young TIL and IL-2 after lymphodepletion with NMA and 6 Gy of total body irradiation. Results: Young TIL cultures for therapy were successfully established from 83% of 122 consecutive melanoma patients. Nineteen of 33 patients (58%) treated with CD8+ enriched young TIL and NMA had an objective response (Response Evaluation Criteria in Solid Tumors) including 3 complete responders. Eleven of 23 patients (48%) treated with TIL and 6 Gy total body irradiation had an objective response including 2 complete responders. At 1 month after TIL infusion the absolute CD8+ cell numbers in the periphery were highly correlated with response. Conclusions: This study shows that a rapid and simplified method can be used to reliably generate CD8+ enriched young TIL for administration as an individualized therapy for advanced melanoma, and may allow this potentially effective treatment to be applied at other institutions and to reach additional patients.

Original languageEnglish (US)
Pages (from-to)6122-6131
Number of pages10
JournalClinical Cancer Research
Volume16
Issue number24
DOIs
StatePublished - Dec 15 2010
Externally publishedYes

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Tumor-Infiltrating Lymphocytes
Melanoma
Interleukin-2
Whole-Body Irradiation
Therapeutics
Neoplasms
Research Design
Cell Count

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dudley, M. E., Gross, C. A., Langhan, M. M., Garcia, M. R., Sherry, R. M., Yang, J. C., ... Rosenberg, S. A. (2010). CD8+ enriched "Young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clinical Cancer Research, 16(24), 6122-6131. https://doi.org/10.1158/1078-0432.CCR-10-1297

CD8+ enriched "Young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. / Dudley, Mark E.; Gross, Colin A.; Langhan, Michelle M.; Garcia, Marcos R.; Sherry, Richard M.; Yang, James C.; Phan, Giao Q.; Kammula, Udai S.; Hughes, Marybeth S.; Citrin, Deborah E.; Restifo, Nicholas P.; Wunderlich, John R.; Prieto, Peter A.; Hong, Jenny J.; Langan, Russell C.; Zlott, Daniel A.; Morton, Kathleen E.; White, Donald E.; Laurencot, Carolyn M.; Rosenberg, Steven A.

In: Clinical Cancer Research, Vol. 16, No. 24, 15.12.2010, p. 6122-6131.

Research output: Contribution to journalArticle

Dudley, ME, Gross, CA, Langhan, MM, Garcia, MR, Sherry, RM, Yang, JC, Phan, GQ, Kammula, US, Hughes, MS, Citrin, DE, Restifo, NP, Wunderlich, JR, Prieto, PA, Hong, JJ, Langan, RC, Zlott, DA, Morton, KE, White, DE, Laurencot, CM & Rosenberg, SA 2010, 'CD8+ enriched "Young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma', Clinical Cancer Research, vol. 16, no. 24, pp. 6122-6131. https://doi.org/10.1158/1078-0432.CCR-10-1297
Dudley, Mark E. ; Gross, Colin A. ; Langhan, Michelle M. ; Garcia, Marcos R. ; Sherry, Richard M. ; Yang, James C. ; Phan, Giao Q. ; Kammula, Udai S. ; Hughes, Marybeth S. ; Citrin, Deborah E. ; Restifo, Nicholas P. ; Wunderlich, John R. ; Prieto, Peter A. ; Hong, Jenny J. ; Langan, Russell C. ; Zlott, Daniel A. ; Morton, Kathleen E. ; White, Donald E. ; Laurencot, Carolyn M. ; Rosenberg, Steven A. / CD8+ enriched "Young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 24. pp. 6122-6131.
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T1 - CD8+ enriched "Young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma

AU - Dudley, Mark E.

AU - Gross, Colin A.

AU - Langhan, Michelle M.

AU - Garcia, Marcos R.

AU - Sherry, Richard M.

AU - Yang, James C.

AU - Phan, Giao Q.

AU - Kammula, Udai S.

AU - Hughes, Marybeth S.

AU - Citrin, Deborah E.

AU - Restifo, Nicholas P.

AU - Wunderlich, John R.

AU - Prieto, Peter A.

AU - Hong, Jenny J.

AU - Langan, Russell C.

AU - Zlott, Daniel A.

AU - Morton, Kathleen E.

AU - White, Donald E.

AU - Laurencot, Carolyn M.

AU - Rosenberg, Steven A.

PY - 2010/12/15

Y1 - 2010/12/15

N2 - Purpose: Tumor-infiltrating lymphocytes (TIL) and interleukin (IL)-2 administered following lymphodepletion can cause the durable complete regression of bulky metastatic melanoma in patients refractory to approved treatments. However, the generation of a unique tumor-reactive TIL culture for each patient may be prohibitively difficult. We therefore investigated the clinical and immunologic impact of unscreened, CD8+ enriched "young" TIL. Experimental Design: Methods were developed for generating TIL that minimized the time in culture and eliminated the individualized tumor-reactivity screening step. Thirty-three patients were treated with these CD8+ enriched young TIL and IL-2 following nonmyeloablative lymphodepletion (NMA). Twenty-three additional patients were treated with CD8+ enriched young TIL and IL-2 after lymphodepletion with NMA and 6 Gy of total body irradiation. Results: Young TIL cultures for therapy were successfully established from 83% of 122 consecutive melanoma patients. Nineteen of 33 patients (58%) treated with CD8+ enriched young TIL and NMA had an objective response (Response Evaluation Criteria in Solid Tumors) including 3 complete responders. Eleven of 23 patients (48%) treated with TIL and 6 Gy total body irradiation had an objective response including 2 complete responders. At 1 month after TIL infusion the absolute CD8+ cell numbers in the periphery were highly correlated with response. Conclusions: This study shows that a rapid and simplified method can be used to reliably generate CD8+ enriched young TIL for administration as an individualized therapy for advanced melanoma, and may allow this potentially effective treatment to be applied at other institutions and to reach additional patients.

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