Autoimmunity associated with immunotherapy of cancer

Amos, Sally M; Duong, Connie P.M.; Westwood, Jennifer A.; Ritchie, David; Junghans, Richard P.; Darcy, Phillip K.; Kershaw, Michael H.

doi:10.1182/blood-2011-01-325266

Cited by 157 publications

(105 citation statements)

References 120 publications

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“…They can avoid the problems associated with antibodies while retaining their functionality. Small molecules can provide increased oral bioavailability, increased bio-efficiency and shortened half-life activity for a more controllable treatment, particularly, in the case of autoimmune or other adverse events [17,18]. Small molecules can also offer greater distribution within the tumor tissue, can cross the bloodbrain-barrier to treat brain tumors, have higher stability at ambient temperature facilitating purification during production.…”

Section: Pharmaceutical Care and Health Systemsmentioning

confidence: 99%

“…These antibodies require bolus intravenous injections every 3 weeks, are administered in high dose and have a long half-life. They cannot be quickly withdrawn from the body if adverse events occur (such as autoimmunity) [17,18]. For example, treatment with antibodies targeting CTLA-4 results in life-threatening autoimmune colitis in 5-10% of patients46 and treatment-related fatalities, while rare, continue to be reported.…”

Section: Pharmaceutical Care and Health Systemsmentioning

confidence: 99%

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Do We Need Small Molecule Inhibitors for the Immune Checkpoints?

Barakat¹

2014

J Pharma Care Health Sys

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Pharmaceutical Care & Health SystemsT lymphocytes preserve the immunological balance between defending against cancer and preventing continual activated immune responses. The balance between the two extremes requires an intricate network of protein-protein interactions (PPIs) that can either inhibit T cell-mediated immune responses targeted against self-antigens or stimulate them to defend against cancer [1]. While T cells' specificity against cancer is determined by the interaction between the T-cell receptor complex (TCR) and antigenic peptides bound in surface major histocompatibility complex (MHC) molecules, the full activation of T cells requires a second signal obtained by the binding of the co-receptor CD28 on T cells to CD80/86molecules on activated antigen presenting cells (APCs). Once mobilized, T cells also express other receptors that inhibit their proliferation and cytokine production. Among these receptors are three immune inhibitory checkpoints: Cytotoxic T Lymphocyte Antigen-4 (CTLA-4), programmed death-1 (PD-1) and T cell immunoglobulin mucin-3 (TIM-3). Tumors can evade the immune system via inhibitory checkpoints to attenuate T cells' signaling, leading to a state of immune tolerance [2]. Blocking the immune inhibitory checkpoints pathways recently emerged as a 'game changer' approach in cancer immunotherapy [3][4][5], with antibodies directed toward PD-1, for example, being selected as 'drug of the year' for 2013 by Science6. These antibodies proved the concept of restoring exhausted T cells' functions and reactivating the immune system to recognize and kill tumor cells [6,7]. More importantly, combination blockage of multiple co-inhibitory pathways has a greater efficacy by preventing accumulation of the unblocked negative co-receptor, allowing T cells to continue to survive, proliferate, and carry out effector functions within the tumor [8][9][10][11][12][13][14][15][16]. However, despite their outstanding success, they still have numerous disadvantages. These agents are monoclonal antibodies and are very expensive to manufacture and administer, making them financially inaccessible to many. For example, under current market conditions, the treatment cost per quality-adjusted life year (QALY) for a patient with metastatic melanoma exceeds $500 000 (USD). These antibodies require bolus intravenous injections every 3 weeks, are administered in high dose and have a long half-life. They cannot be quickly withdrawn from the body if adverse events occur (such as autoimmunity) [17,18]. For example, treatment with antibodies targeting CTLA-4 results in life-threatening autoimmune colitis in 5-10% of patients46 and treatment-related fatalities, while rare, continue to be reported. These limitations suggest that the full potential of the immune checkpoint blockade has yet to be fulfilled and raise an urgent need to explore new modalities that can target the same pathways, but be safer and more effective.Small molecules can provide this safe therapeutic alternative. They can avoid the problems associate...

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Section: Pharmaceutical Care and Health Systemsmentioning

confidence: 99%

Section: Pharmaceutical Care and Health Systemsmentioning

confidence: 99%

Do We Need Small Molecule Inhibitors for the Immune Checkpoints?

Barakat¹

2014

J Pharma Care Health Sys

View full text Add to dashboard Cite

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“…First, toxicity can follow the induction of potent endogenous autoimmunity against both tumor antigens and other self-antigens, resulting in both on-and off-target toxicities. Second, toxicities can involve on-target depletion of normal cell subsets, compromising normal tissue function [5]. CTLA-4 is a regulatory molecule expressed by T cells that transmits an inhibitory signal to T cells on binding to CD80 and CD86 on antigen-presenting cells.…”

Section: Pathogenesismentioning

confidence: 99%

“…Components of immunity are seen as potentially more specific weapons to direct against tumors than chemotherapy or radiation [5]. With our expanding knowledge of tumor associated antigens (TAAs), there are many different approaches being developed to direct immunity against transformed cells.…”

Section: Introductionmentioning

confidence: 99%

A Review on Clinicopathological Correlation between Classical Inflammatory Bowel Disease and Immunotherapy Related Inflammatory Bowel Disease

Allen¹

2014

Immunome Res

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Blockade of various immune targets such as cytotoxic T-lymphocyte antigen-4 and Programmed cell death leads to immune-mediated tumor regression and immune-related adverse events, predominantly gastrointestinal events including diarrhea and colitis. The current review is done to understand the underlying mechanism of action and to identify potential biomarkers that could help in the prediction and management of gastrointestinal immune-related adverse events. Histological assessment of bowel biopsies and assessment of serologic markers of inflammatory bowel disease and colitis secondary to immune mediated antibodies are reviewed. Ipilimumab causes dysregulation of gastrointestinal mucosal immunity, which can be evidenced by altered antibody levels to enteric flora and inflammatory cell infiltration into gastrointestinal mucosa associated with diarrhea and clinical evidence of colitis. The pattern of drug induced antibody titers to microbial flora and the histological features and location of the inflammation were distinct from classic inflammatory bowel disease. Although classic inflammatory bowel disease and immune mediated antibodies related gastrointestinal toxicity are both immune mediated, the pattern of biomarkers and histological features suggests that the later may be a distinct clinicopathologic entity.

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“…However, recent developments show that using CTL engineered to recognize TAA with high avidity attracts considerable risks. The use of CTL with artificially enhanced TCR affinity was associated with dangerous toxicity (8) caused by CTL recognizing the TAA, or a closely related Ag, on normal tissues. An extreme example is the fatal encephalitis and cardiotoxicity elicited following transfer of CTL engineered to target MAGE-A3 with high affinity (9,10).…”

mentioning

confidence: 99%

Target Density, Not Affinity or Avidity of Antigen Recognition, Determines Adoptive T Cell Therapy Outcomes in a Mouse Lymphoma Model

Segal

Prato

Zehn

et al. 2016

The Journal of Immunology

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Adoptive T cell therapy (ACT) with antitumor CTL is a promising and tailored treatment against cancer. We investigated the role played by the affinity and avidity of the interaction between the tumor and the CTL on the outcome of ACT against a mouse non-Hodgkin B cell lymphoma that expresses OVA as a model neoantigen. ACT was assessed under conditions where antitumor CTL expressed TCR of varying affinity for OVA. We also assessed conditions where the avidity of Ag recognition varied because the lymphoma cells expressed high or low levels of OVA. Efficient eradication of small tumor burdens was achieved by high- or low-affinity CTL. Tumors expressing low levels of OVA could also be eliminated. However, ACT against large tumor burdens was unsuccessful, accompanied by CTL deletion and functional impairment. This negative outcome was not prevented by lowering the affinity of the CTL or the expression of OVA in the lymphoma. Thus, tumor burden, rather than CTL affinity or avidity, appears to be the main determinant of ACT outcomes in our lymphoma model. Insofar as our results can be extrapolated to the clinical setting, they imply that the range of CTL and tumor-associated Ag combinations that may be effectively harnessed in ACT against lymphoma may be wider than generally assumed. CTL expressing low-affinity TCR may be effective against lymphoma, and lowly expressed tumor-associated Ag should be considered as potential targets, but tumor reduction should always be implemented before infusion of the CTL.

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Autoimmunity associated with immunotherapy of cancer

Cited by 157 publications

References 120 publications

Do We Need Small Molecule Inhibitors for the Immune Checkpoints?

Do We Need Small Molecule Inhibitors for the Immune Checkpoints?

A Review on Clinicopathological Correlation between Classical Inflammatory Bowel Disease and Immunotherapy Related Inflammatory Bowel Disease

Target Density, Not Affinity or Avidity of Antigen Recognition, Determines Adoptive T Cell Therapy Outcomes in a Mouse Lymphoma Model

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