Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients

F. Stephen Hodi, Martin C. Mihm, Robert J. Soiffer, Frank G. Haluska, Marcus Butler, Michael V. Seiden, Thomas Davis, Rochele Henry-Spires, Suzanne MacRae, Ann Willman, Robert Padera, Michael T. Jaklitsch, Sridhar Shankar, Teresa C. Chen, Alan Korman, James P. Allison, Glenn Dranoff

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Abstract

A large number of cancer-associated gene products evoke immune recognition, but host reactions rarely impede disease progression. The weak immunogenicity of nascent tumors contributes to this failure in host defense. Therapeutic vaccines that enhance dendritic cell presentation of cancer antigens increase specific cellular and humoral responses, thereby effectuating tumor destruction in some cases. The attenuation of T cell activation by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) further limits the potency of tumor immunity. In murine systems, the administration of antibodies that block CTLA-4 function inhibits the growth of moderately immunogenic tumors and, in combination with cancer vaccines, increases the rejection of poorly immunogenic tumors, albeit with a loss of tolerance to normal differentiation antigens. To gain a preliminary assessment of the biologic activity of antagonizing CTLA-4 function in humans, we infused a CTLA-4 blocking antibody (MDX-CTLA4) into nine previously immunized advanced cancer patients. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three of three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two of two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous granulocyte-macrophage colony-stimulating factor-secreting tumor cells. MDX-CTLA4 did not elicit tumor necrosis in four of four metastatic melanoma patients previously immunized with defined melanosomal antigens. No serious toxicities directly attributable to the antibody were observed, although five of seven melanoma patients developed T cell reactivity to normal melanocytes. These findings suggest that CTLA-4 antibody blockade increases tumor immunity in some previously vaccinated cancer patients.

Original languageEnglish (US)
Pages (from-to)4712-4717
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number8
DOIs
StatePublished - Apr 15 2003

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CTLA-4 Antigen
Melanoma
Carcinoma
Antibodies
Neoplasms
Immunity
Necrosis
T-Lymphocytes
Cancer Vaccines
Blocking Antibodies
Neoplasm Genes
Melanocytes
Differentiation Antigens
Antigen Presentation
Granulocyte-Macrophage Colony-Stimulating Factor
Granulocytes
Dendritic Cells
Disease Progression

All Science Journal Classification (ASJC) codes

  • General

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Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. / Hodi, F. Stephen; Mihm, Martin C.; Soiffer, Robert J.; Haluska, Frank G.; Butler, Marcus; Seiden, Michael V.; Davis, Thomas; Henry-Spires, Rochele; MacRae, Suzanne; Willman, Ann; Padera, Robert; Jaklitsch, Michael T.; Shankar, Sridhar; Chen, Teresa C.; Korman, Alan; Allison, James P.; Dranoff, Glenn.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 8, 15.04.2003, p. 4712-4717.

Research output: Contribution to journalArticle

Hodi, FS, Mihm, MC, Soiffer, RJ, Haluska, FG, Butler, M, Seiden, MV, Davis, T, Henry-Spires, R, MacRae, S, Willman, A, Padera, R, Jaklitsch, MT, Shankar, S, Chen, TC, Korman, A, Allison, JP & Dranoff, G 2003, 'Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 8, pp. 4712-4717. https://doi.org/10.1073/pnas.0830997100
Hodi, F. Stephen ; Mihm, Martin C. ; Soiffer, Robert J. ; Haluska, Frank G. ; Butler, Marcus ; Seiden, Michael V. ; Davis, Thomas ; Henry-Spires, Rochele ; MacRae, Suzanne ; Willman, Ann ; Padera, Robert ; Jaklitsch, Michael T. ; Shankar, Sridhar ; Chen, Teresa C. ; Korman, Alan ; Allison, James P. ; Dranoff, Glenn. / Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 8. pp. 4712-4717.
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abstract = "A large number of cancer-associated gene products evoke immune recognition, but host reactions rarely impede disease progression. The weak immunogenicity of nascent tumors contributes to this failure in host defense. Therapeutic vaccines that enhance dendritic cell presentation of cancer antigens increase specific cellular and humoral responses, thereby effectuating tumor destruction in some cases. The attenuation of T cell activation by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) further limits the potency of tumor immunity. In murine systems, the administration of antibodies that block CTLA-4 function inhibits the growth of moderately immunogenic tumors and, in combination with cancer vaccines, increases the rejection of poorly immunogenic tumors, albeit with a loss of tolerance to normal differentiation antigens. To gain a preliminary assessment of the biologic activity of antagonizing CTLA-4 function in humans, we infused a CTLA-4 blocking antibody (MDX-CTLA4) into nine previously immunized advanced cancer patients. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three of three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two of two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous granulocyte-macrophage colony-stimulating factor-secreting tumor cells. MDX-CTLA4 did not elicit tumor necrosis in four of four metastatic melanoma patients previously immunized with defined melanosomal antigens. No serious toxicities directly attributable to the antibody were observed, although five of seven melanoma patients developed T cell reactivity to normal melanocytes. These findings suggest that CTLA-4 antibody blockade increases tumor immunity in some previously vaccinated cancer patients.",
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AU - Hodi, F. Stephen

AU - Mihm, Martin C.

AU - Soiffer, Robert J.

AU - Haluska, Frank G.

AU - Butler, Marcus

AU - Seiden, Michael V.

AU - Davis, Thomas

AU - Henry-Spires, Rochele

AU - MacRae, Suzanne

AU - Willman, Ann

AU - Padera, Robert

AU - Jaklitsch, Michael T.

AU - Shankar, Sridhar

AU - Chen, Teresa C.

AU - Korman, Alan

AU - Allison, James P.

AU - Dranoff, Glenn

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N2 - A large number of cancer-associated gene products evoke immune recognition, but host reactions rarely impede disease progression. The weak immunogenicity of nascent tumors contributes to this failure in host defense. Therapeutic vaccines that enhance dendritic cell presentation of cancer antigens increase specific cellular and humoral responses, thereby effectuating tumor destruction in some cases. The attenuation of T cell activation by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) further limits the potency of tumor immunity. In murine systems, the administration of antibodies that block CTLA-4 function inhibits the growth of moderately immunogenic tumors and, in combination with cancer vaccines, increases the rejection of poorly immunogenic tumors, albeit with a loss of tolerance to normal differentiation antigens. To gain a preliminary assessment of the biologic activity of antagonizing CTLA-4 function in humans, we infused a CTLA-4 blocking antibody (MDX-CTLA4) into nine previously immunized advanced cancer patients. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three of three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two of two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous granulocyte-macrophage colony-stimulating factor-secreting tumor cells. MDX-CTLA4 did not elicit tumor necrosis in four of four metastatic melanoma patients previously immunized with defined melanosomal antigens. No serious toxicities directly attributable to the antibody were observed, although five of seven melanoma patients developed T cell reactivity to normal melanocytes. These findings suggest that CTLA-4 antibody blockade increases tumor immunity in some previously vaccinated cancer patients.

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