Cytotoxic T-Lymphocyte-Associated Antigen-4 Blockage Can Induce Autoimmune Hypophysitis in Patients With Metastatic Melanoma and Renal Cancer

Blansfield, Joseph; Beck, Kimberly E.; Tran, Khoi Q.; Yang, James Chih‐Hsin; Hughes, Marybeth S.; Kammula, Udai S.; Royal, Richard E.; Topalian, Suzanne L.; Haworth, Leah; Lévy, Catherine; Rosenberg, Steven A.; Sherry, Richard M.

doi:10.1097/01.cji.0000178913.41256.06

Cited by 326 publications

(255 citation statements)

References 17 publications

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“…They are also being used in combination with tumour vaccines (peptides) [9,10] or various forms of chemotherapy (http://clinicaltrials.gov/). Importantly, tumour responses often develop over an extended period of weeks or months and tend to correlate with autoimmune manifestations and systemic inflammation, seen in at least a third of patients [11,12].…”

Section: Introductionmentioning

confidence: 99%

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

et al. 2008

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Immunostimulatory mAb as vaccine adjuvants for the treatment of cancer hold considerable potential for boosting weak responses when used against immunogenic tumours, or in combination with various other vaccines. We now show that when administered with OVA, the combination of anti-4-1BB mAb with anti-CD40, anti-OX40 or anti-CD25 resulted in a fourfold enhancement in the antigen-specific T-cell response compared with anti-4-1BB mAb alone, with a similar enhancement in memory responses following rechallenge with OVA. Although the number of antigen-specific T-cells generated after treatment with each of the combinations was similar, marked functional differences were detected. In particular, anti-4-1BB/anti-CD25 resulted in excellent expansion of specific CD81 T cells but produced fewer IFN-c-secreting effector cells than the other combinations. Anti-4-1BB/anti-OX40 proved to be the most potent, inducing the most effective T-cell responses in the RIPmOVA diabetes model with adoptively transferred OVA-specific T cells, and, when given with a peptide vaccine, protecting mice against the poorly immunogenic B16-F10 tumour. Overall the results suggest that although these combinations of mAb look promising in terms of their therapeutic potential, further functional assays are needed to compare their effects.

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Section: Introductionmentioning

confidence: 99%

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

et al. 2008

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“…16,17 Also, CTLA-4 blockade, alone or in combination with other immunointerventions, [18][19][20][21][22][23] can lead to rejection of transplanted tumor cell lines in mice, and this observation has recently led to phase I clinical trials with anti-human CTLA-4 monoclonal antibodies (mAb) in patients with melanoma or ovarian carcinoma. [24][25][26][27] In a mouse model of major histocompatibility (MHC) mismatched bone marrow transplantation (BMT), early CTLA-4 blockade enhanced alloreactivity, resulting in either GVHD or graft rejection. Later after BMT, CTLA-4 blockade in conjunction with donor lymphocyte infusion (DLI) elicited a significant antitumor effect, but severe GVHD precluded a survival advantage.…”

Section: Introductionmentioning

confidence: 99%

CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease

et al. 2007

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We studied the effect of CTLA-4 blockade on graft-versusleukemia and graft-versus-host responses in a mouse model of minor histocompatibility-mismatched bone marrow transplantation. Early CTLA-4 blockade induced acute graft-versus-host disease. Delayed CTLA-4 blockade resulted in a lethal condition with lymphosplenomegaly, but with stable mixed T-cell chimerism, unchanged alloreactive T-cell frequencies and absent anti-host reactivity in vitro. In contrast, multiorgan lymphoproliferative disease with autoimmune hepatitis and circulating anti-DNA auto-antibodies were documented. Splenic lymphocytes exhibited ex vivo spontaneous proliferation and a marked proliferative response against host-type dendritic cells pulsed with syngeneic (host-type) tissue-peptides. Both phenomena were exclusively mediated by host and not donor T cells, supporting an autoimmune pathogenesis. Selectively hostderived T-cell immune reactivity was equally documented against leukemia-peptide-pulsed dendritic cells, and this was paralleled by a strong in vivo antileukemic effect in anti-CTLA-4-treated and subsequently leukemia-challenged chimeras. In conclusion, delayed CTLA-4 blockade induced a host-derived antileukemic effect, occurring in the context of an autoimmune syndrome and strictly separated from graft-versus-host disease. Both antileukemic and autoimmune responses depended on the allogeneic component, as neither effect was seen after syngeneic bone marrow transplantation. Our findings reveal the potential of using CTLA-4 blockade to establish antileukemic effects after allogeneic hematopoietic stem cell transplantation, provided autoimmunity can be controlled.

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“…Recovery of the pituitary thyroid axis has been reported in 37-50%, whereas gonadal axis may recover in over 50% of cases. 2,12 Corticotroph function appears to be persistently affected, so very few patients might be able to discontinue glucocorticoid replacement. 2,7 Pituitary hormone deficiencies should be periodically re-evaluated after the radiological resolution of AH.…”

Section: Discussionmentioning

confidence: 99%

“…The height of pituitary may increase modestly, from 3.4 mm -6.0 mm to 7.7 mm -11.8 mm. 1,[11][12][13] Pituitary enlargement is a highly sensitive indicator of ipilimumab-induced AH and may cause compression of optic chiasm and visual defects, although this situation is rarely seen. 2,6,7 A metastatic lesion must be considered in patients with malignant melanoma with evidence of pituitary enlargement (with or without hypopituitarism).…”

Section: Discussionmentioning

confidence: 99%

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Ipilimumab-Induced Autoimmune Hypophysitis: Diagnostic and Management Challenges Illustrated by a Clinical Case

Marques¹,

Grossman²

2015

Acta Med Port

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775Marques P, et al. Ipilimumab-induced autoimmune hypophysitis, Acta Med Port 2015 Nov-Dec;28(6):775-779 decíduos e às consequências da sua extração precoce, este RN deverá ser acompanhado por Odontopediatria.A exodontia deve ser evitada durante os primeiros dez dias de vida do RN, devido à incapacidade de produção de vitamina K, necessária ao processo hemostático. 3,7 Encontrando-se o RN no 16º dia de vida, procedeu-se a exodontia com segurança, com a colaboração da Cirurgia Maxilo-Facial.Dada a raridade deste distúrbio, ressalva-se a importância deste caso, que representa, segundo a literatura consultada, o terceiro caso a ser reportado de dente neonatal em RN prematuro. O conhecimento dos Pediatras sobre este distúrbio de erupção dentária é fulcral, contribuindo para uma correta e precoce intervenção. PROTECÇÃO DE PESSOAS E ANIMAISOs autores declaram que os procedimentos seguidos estavam de acordo com os regulamentos estabelecidos pelos responsáveis da Comissão de Investigação Clínica e Ética e de acordo com a Declaração de Helsínquia da Associação Médica Mundial. CONFIDENCIALIDADE DOS DADOSOs autores declaram ter seguido os protocolos do seu centro de trabalho acerca da publicação dos dados de doentes. CONFLITOS DE INTERESSENão existem conflitos de interesse a declarar. FONTES DE FINANCIAMENTONão foi recebido qualquer subsídio ou bolsa. ABSTRACT Autoimmune hypophysitis has been described in patients on ipilimumab, a humanised monoclonal antibody increasingly used in the treatment of metastatic melanoma. A 67-year-old woman presented with severe fatigue, nausea and headaches following the third dose of ipilimumab, which was being given as treatment for metastatic melanoma (four administrations at three-weekly intervals). Hormonal evaluation confirmed hypocortisolism, with low gonadotrophins and a low thyroid-stimulating hormone with normal free T4 (she was on long-standing levothyroxine because of past surgery for a multinodular goitre). Magnetic resonance imaging scanning revealed pituitary enlargement compatible with autoimmune hypophysitis. She was commenced on replacement with hydrocortisone with significant improvement of her symptoms. The enlarged pituitary was reduced in size 4 months later. The patient is currently asymptomatic on glucocorticoid and levothyroxine replacement. This case highlights relevant clinical, diagnostic and management aspects of ipilimumab-induced autoimmune hypophysitis, and emphasises the need for increasing awareness for potential side-effects of these new immunomodulatory therapies, including autoimmune hypophysitis. REFERÊNCIAS

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Cytotoxic T-Lymphocyte-Associated Antigen-4 Blockage Can Induce Autoimmune Hypophysitis in Patients With Metastatic Melanoma and Renal Cancer

Cited by 326 publications

References 17 publications

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease

Ipilimumab-Induced Autoimmune Hypophysitis: Diagnostic and Management Challenges Illustrated by a Clinical Case

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