Phase II study of intermittent continuous infusion of low-dose recombinant interleukin-2 in advanced melanoma and renal cell cancer

Vlasveld, L. T.; Horenblas, Simon; Hekman, Annemarie; Hilton, Anne; Dubbelman, Anne-Charlotte; Melief, C. J. M.; Rankin, E. M.

doi:10.1093/oxfordjournals.annonc.a058774

Cited by 21 publications

(8 citation statements)

References 6 publications

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“…In the absence of any serious toxicity, the last six patients received very low-dose IL-2 at 2.5×10 5 U/m 2 twice-daily s.c. for 14 days following each T cell infusion as a source of helper support. The dose of IL-2 used is sufficient to saturate the high-affinity IL-2 receptor in vivo , and, when administered alone, has no anti-melanoma effect and minimal toxicity[13]. Twenty-one days after the first T cell infusion, patients received fludarabine conditioning at 25 mg/m 2 /day consecutively for five days.…”

Section: Methodsmentioning

confidence: 99%

Fludarabine Modulates Immune Response and Extends In Vivo Survival of Adoptively Transferred CD8 T Cells in Patients with Metastatic Melanoma

et al. 2009

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BackgroundAdoptive T cell therapy involving the use of ex vivo generated antigen-specific cytotoxic T lymphocytes provides a promising approach to immunotherapy. It has become increasingly apparent that anti-tumor efficacy using adoptively transferred T cells is linked to their duration of in vivo persistence and can only be achieved when combined with some form of pre-infusion patient conditioning regimen. An optimal conditioning regimen that provides a positive benefit without serious toxicities has yet to be defined. We have established a unique clinical model that allows for evaluation of a given conditioning regimen on adoptively transferred T cells in humans. In this first-in-human study (FHCRC #1796), we evaluate the use of fludarabine, an FDA-approved reagent with predictable lymphodepleting kinetics and duration of action, as a conditioning regimen that promotes homeostatic upregulation of cytokines and growth signals contributing to in vivo T cell persistence.Methods/FindingsWe conducted a phase I study in patients with refractory metastatic melanoma. Patients received two infusions of a single tumor-reactive antigen-specific CTL clone expanded to 1010/m2; the first infusion was given without fludarabine conditioning, and the second CTL infusion was given after a course of fludarabine (25 mg/m2/day×5 days). This design permits intra-patient comparison of in vivo T cell persistence pre- and post-fludarabine. Nineteen CTL infusions were administered to ten patients. No serious toxicities were observed. Three of nine evaluable patients experienced minor response or stable disease for periods of 5.8–11.0 months with two additional patients demonstrating delayed disease stabilization. The median overall survival in this heavily pre-treated population was 9.7 months. Fludarabine led to a 2.9 fold improvement in the in vivo persistence of transferred CTL clones from a median of 4.5 days (range 0–38+) to 13.0 days (range 2–63+) (p<0.05). Fludarabine lymphodepletion increased plasma levels of the homeostatic cytokines IL-7 and IL-15. Surprisingly, fludarabine also increased the relative percentage of CD4+ T cells expressing the regulatory protein Foxp3.Conclusions/SignificanceLymphodepletion with fludarabine enhances transferred T cell persistence but suggest that additional improvements to optimize T cell survival and address regulatory T cells are critical in providing anti-tumor efficacy.Trial RegistrationClinicalTrials.gov NCT00317759

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Section: Methodsmentioning

confidence: 99%

Fludarabine Modulates Immune Response and Extends In Vivo Survival of Adoptively Transferred CD8 T Cells in Patients with Metastatic Melanoma

et al. 2009

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“…Stopping rules included the appearance of serious (Նgrade III toxicity by National Cancer Institute common toxicity criteria). The dose of IL-2 used is sufficient to saturate high-affinity IL-2 receptors in vivo and, when administered alone, has no anti-melanoma effect and minimal toxicity (12,13). tide were expressed in Escherichia coli and refolded together in vitro in the presence of peptide and biotinylated.…”

Section: Generation Of Mart-1 and Gp100-specific Cd8 ؉ T Cell Clones mentioning

confidence: 99%

Adoptive T cell therapy using antigen-specific CD8⁺T cell clones for the treatment of patients with metastatic melanoma:In vivopersistence, migration, and antitumor effect of transferred T cells

Yee

Thompson

Byrd

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

1,070

799

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Adoptive T cell therapy, involving the ex vivo selection and expansion of antigen-specific T cell clones, provides a means of augmenting antigen-specific immunity without the in vivo constraints that can accompany vaccine-based strategies. A phase I study was performed to evaluate the safety, in vivo persistence, and efficacy of adoptively transferred CD8 ؉ T cell clones targeting the tumor-associated antigens, MART1͞MelanA and gp100 for the treatment of patients with metastatic melanoma. Four infusions of autologous T cell clones were administered, the first without IL-2 and subsequent infusions with low-dose IL-2 (at 0.25, 0.50, and 1.0 ؋ 10 6 units͞m 2 twice daily for the second, third, and fourth infusions, respectively). Forty-three infusions of MART1͞MelanA-specific or gp100-specific CD8 ؉ T cell clones were administered to 10 patients. No serious toxicity was observed. We demonstrate that the adoptively transferred T cell clones persist in vivo in response to low-dose IL-2, preferentially localize to tumor sites and mediate an antigen-specific immune response characterized by the elimination of antigen-positive tumor cells, regression of individual metastases, and minor, mixed or stable responses in 8 of 10 patients with refractory, metastatic disease for up to 21 mo.

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“…Lower doses of IL-2 alone, either i.v. or subcutaneously (s.c.), are considered to yield responses only rarely (Vlasveld et al, 1994).…”

mentioning

confidence: 99%

Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma

Lotem¹,

Shiloni

Pappo

et al. 2004

Br J Cancer

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This paper is a report of response rate (RR) and survival of 34 metastatic melanoma patients who received a dinitrophenyl (DNP)-modified autologous melanoma cell vaccine. In all, 27 patients started the vaccine as a primary treatment for metastatic melanoma and seven started it as an adjuvant, with no evidence of disease at the time, but had developed new metastases. Interleukin-2 (IL-2) was administered in 24 out of the 34 patients: 19 who progressed on vaccine alone and five who had the combination from start. Interleukin-2 was administered in the intravenous, bolus high-dose regimen (seven patients) or as subcutaneous (s.c.) low-dose treatment (17). Overall response for the entire group was 35% (12 patients out of 34), 12% having a complete response (CR) and 23% a partial response (PR). However, only two patients had tumour responses while on the vaccine alone, whereas the other 10 demonstrated objective tumour regression following the combination with IL-2 (two CR, eight PR), lasting for a median duration of 6 months (range 3 -50 months). Of the 12 responding patients, 11 attained strong skin reactivity to the s.c. injection of irradiated, unmodified autologous melanoma cells. None of the patients with a negative reactivity experienced any tumour response. Patients with positive skin reactions survived longer (median survival -54 months). The results suggest enhanced RRs to the combination of IL-2 and autologous melanoma vaccine. Skin reactivity to unmodified autologous melanoma cells may be a predictor of response and improved survival, and therefore a criterion for further pursuing of immunotherapeutic strategies.

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Phase II study of intermittent continuous infusion of low-dose recombinant interleukin-2 in advanced melanoma and renal cell cancer

Abstract: Intermittent continuous infusion of low dose rIL-2 in advanced melanoma and renal cell cancer is well tolerated but the initial therapeutic results are not promising.

Cited by 21 publications

References 6 publications

Fludarabine Modulates Immune Response and Extends In Vivo Survival of Adoptively Transferred CD8 T Cells in Patients with Metastatic Melanoma

Fludarabine Modulates Immune Response and Extends In Vivo Survival of Adoptively Transferred CD8 T Cells in Patients with Metastatic Melanoma

Adoptive T cell therapy using antigen-specific CD8⁺T cell clones for the treatment of patients with metastatic melanoma:In vivopersistence, migration, and antitumor effect of transferred T cells

Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma

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Phase II study of intermittent continuous infusion of low-dose recombinant interleukin-2 in advanced melanoma and renal cell cancer

Abstract: Intermittent continuous infusion of low dose rIL-2 in advanced melanoma and renal cell cancer is well tolerated but the initial therapeutic results are not promising.

Cited by 21 publications

References 6 publications

Fludarabine Modulates Immune Response and Extends In Vivo Survival of Adoptively Transferred CD8 T Cells in Patients with Metastatic Melanoma

Fludarabine Modulates Immune Response and Extends In Vivo Survival of Adoptively Transferred CD8 T Cells in Patients with Metastatic Melanoma

Adoptive T cell therapy using antigen-specific CD8+T cell clones for the treatment of patients with metastatic melanoma:In vivopersistence, migration, and antitumor effect of transferred T cells

Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma

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Adoptive T cell therapy using antigen-specific CD8⁺T cell clones for the treatment of patients with metastatic melanoma:In vivopersistence, migration, and antitumor effect of transferred T cells