Cytotoxic T Lymphocyte-Associated Antigen 4 Blockade in Patients with Metastatic Melanoma

Robinson, Michael R.; Chan, Chi Chao; Yang, James Chih‐Hsin; Rubin, Betty L.; Gracia, Gerald; Sen, H. Nida; Csaky, Karl G.; Rosenberg, Steven A.

doi:10.1097/00002371-200411000-00008

Cited by 146 publications

(81 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…52 In phase I clinical trials, the combination of melanoma vaccines with anti-CTLA-4 mAb induced cancer regression, but with antinuclear Ab and autoimmune manifestations in colon, liver, skin, eye and pituitary glands as side effects. [24][25][26][27]53 The immunopathogenesis of the observed autoimmune condition is as yet not resolved but the subject of ongoing studies. Our data suggest that mechanisms of self-tolerance and transplant rejection are differentially affected by delayed and early CTLA-4 blockade.…”

Section: Discussionmentioning

confidence: 99%

“…However, the antileukemic benefit was offset by autoimmune mortality. Strategies to control autoimmunity while preserving GVL, as recently demonstrated in mouse and patient studies of anti-CTLA-4 therapy for solid tumors, [24][25][26][27]53,67,68 are currently being explored. Our data provide evidence that CTLA-4 blockade represents a potentially valuable target for the design of adjuvant immunotherapy after allogeneic HSCT for leukemia.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2007

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Infiltrates of CD4 and CD8 T cells can be observed in skin and colon biopsies. Other serious adverse events include hypophysitis, uveitis, and hepatitis Phan et al, 2003b;Ribas et al, 2005a;Robinson et al, 2004); it is presumed that these events are also the consequence of inflammatory T-cell infiltration. Colectomy has been necessary in some cases of colitis and two deaths were observed in a combination trial with DTIC, although these may be ascribed to causes other than anti-CTLA-4 (Fischkoff et al, 2005;Korman et al, 2005).…”

Section: Clinical Trials Of Ctla-4 Blockade: Adverse Eventsmentioning

confidence: 99%

Checkpoint Blockade in Cancer Immunotherapy

Korman¹,

Peggs

Allison

2006

Advances in Immunology

508

364

View full text Add to dashboard Cite

The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such immunological molecular adjuvants are showing promise in early clinical trials. This review focuses on the results of the archetypal example of checkpoint blockade, anti-CTLA-4, in preclinical tumor models and clinical trials, while also highlighting other possible targets for immunological checkpoint blockade.

show abstract

“…The incidence with anti-PD-1 antibodies is unknown [42,43]. Besides, from the direct toxicity of immunotherapy agents, the eye can also indirectly be afected via other immune-related adverse endocrinopathies such as hyperthyroidism form autoimmune thyroiditis [30,43].…”

Section: Ophthalmologicalmentioning

confidence: 99%

“…Besides, from the direct toxicity of immunotherapy agents, the eye can also indirectly be afected via other immune-related adverse endocrinopathies such as hyperthyroidism form autoimmune thyroiditis [30,43]. There have been case reports of Grave's opthalmopathy with symptoms and signs of proptosis associated with swelling of extraocular muscles and xeropthalmia [30,42,44]. Ophthalmological side efects include episcleritis, conjunctivitis, and uveitis [3].…”

Section: Ophthalmologicalmentioning

confidence: 99%

Management and Supportive Care of Patients Undergoing Immunotherapy

Rapoport¹,

Eeden²

2017

Immunotherapy - Myths, Reality, Ideas, Future

View full text Add to dashboard Cite

In many tumor types, where the prognosis was shown to be extremely dismal before, immunotherapy is now a new beacon of hope to many patients. Immunotherapy has been approved for use in a many diferent cancers including metastatic melanoma, advanced non-small cell lung cancer, metastatic renal cell carcinoma, refractory Hodgkin's lymphoma, metastatic bladder cancer advanced head and neck cancer, and the list keeps growing each day. It seems to be generally beter tolerated in most patients and less toxic compared to what we have seen in diferent anticancer treatments from before. However, the toxicities here are termed immune-related adverse events. There is almost no prospective data on these toxicities, and guidelines or recommendations are mostly based on symptomatic management from the ongoing clinical trials. Treating oncologists need to be aware of the subtleties in presentation and the huge diference in the way we mange these side efects. Although most adverse events are low-grade and manageable, they have the potential to be life-threatening if not treated promptly. In this chapter, we address the diferent immune-related adverse events relating to the organ system they can involve, presentation and symptomatology, general recommendations of management, and individual toxicities. Keywords: immunotherapy, PD-1, CTLA-4.

show abstract

Cytotoxic T Lymphocyte-Associated Antigen 4 Blockade in Patients with Metastatic Melanoma

Cited by 146 publications

References 5 publications

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

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

Checkpoint Blockade in Cancer Immunotherapy

Management and Supportive Care of Patients Undergoing Immunotherapy

Contact Info

Product

Resources

About