Is autoimmunity the Achilles' heel of cancer immunotherapy?

June, Carl H.; Warshauer, Jeremy; Bluestone, Jeffrey A.

doi:10.1038/nm.4321

Cited by 388 publications

(324 citation statements)

References 106 publications

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“…Similarly, pronounced bile duct toxicities were observed in a clinical trial using CAR T-cells targeting carbonic anhydrase [78]. In a future in which CAR T-cells may be super-charged against tumors, these toxicities threaten to become commonplace analogous to the surge in autoimmune disease secondary to checkpoint inhibitor therapy in patients today [79]. …”

Section: Engineering Safety and Specificity Into T-cell Therapymentioning

confidence: 99%

Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities

Shum

Kruse²,

Rooney³

2018

Expert Opinion on Biological Therapy

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Introduction: Cancer therapy has been transformed by the demonstration that tumor-specific T-cells can eliminate tumor cells in a clinical setting with minimal long-term toxicity. However significant success in the treatment of leukemia and lymphoma with T-cells using native receptors or redirected with chimeric antigen receptors (CARs) has not been recapitulated in the treatment of solid tumors. This lack of success is likely related to the paucity of costimulatory and cytokine signaling available in solid tumors, in addition to a range of inhibitory mechanisms. Areas covered: We summarize the latest developments in engineered T-cell immunotherapy, describe the limitations of these approaches in treating solid tumors, and finally highlight several strategies that may be useful in mediating solid tumor responses in the future, while also ensuring safety of engineered cells. Expert opinion: CAR-T therapies require further engineering to achieve their potential against solid tumors. Facilitating cytokine signaling in CAR T-cells appears to be essential in achieving better responses. However, the engineering of T-cells with potentially unchecked proliferation and potency raises the question of whether the simultaneous combination of enhancements will prove safe, necessitating continued advancements in regulating CAR-T activity at the tumor site and methods to safely switch off these engineered cells.

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Section: Engineering Safety and Specificity Into T-cell Therapymentioning

confidence: 99%

Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities

Shum

Kruse²,

Rooney³

2018

Expert Opinion on Biological Therapy

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“…Immune system activation leads to rejection of cancer cells but may be harmful to healthy tissues [14]. Common irAEs include cutaneous, gastrointestinal, hepatic, pulmonary, and endocrine events [4–7].…”

Section: Discussionmentioning

confidence: 99%

Treatment of mycophenolate-resistant immune-related organizing pneumonia with infliximab

Sánchez¹,

Jahn²,

Savic³

et al. 2018

j. immunotherapy cancer

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BackgroundThe development of pulmonary immune-related adverse events (irAEs) in patients undergoing PD-(L)1 targeted checkpoint inhibitors are rare, but may be life-threatening. While many published articles and guidelines are focusing on the presentation and upfront treatment of pulmonary irAEs, the strategy in patients with late-onset pneumonia that are resistant to commonly used immunosuppressive drugs remains unclear.Case presentationHere, we report the successful treatment of a mycophenolate-resistant organizing pneumonia (OP) with infliximab in a patient with metastatic melanoma after PD-1 blockade. The patient received two years of PD-1 targeted immunotherapy when he developed multiple nodular lung lesions mimicking a metastatic progression. However, wedge resection of these lesions showed defined areas of OP, which responded well to corticosteroids. Upon tapering, new foci of OP developed which were resistant to high-dose steroids and mycophenolate treatment. The TNFα antagonist infliximab led to a rapid and durable regression of the inflammatory lesions.ConclusionThis case describes a not well-studied situation, in which a mycophenolate-resistant PD-1 blocker-associated pneumonitis was successfully treated with a TNFα neutralizing antibody. The outcome of this case suggests that infliximab might be the preferable option compared to classical immunosuppressants in the case of steroid-resistant/−dependent late onset pulmonary irAEs.

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“…Checkpoint inhibition involving blocking of CTLA-4 can result in enhancement of costimulatory signal, response to overexpressed and tumor antigens and Treg proliferation. [1] PD-1 is another immune checkpoint, operating in the periphery that is a target of monoclonal antibodies Figure 1 that are used to treat various cancers. Anti-PD-1 therapy involves blocking the interaction of PD-1 with its ligands PD-L1 and PD-L2 and removes suppression on T cells, enhancing their proliferation.…”

Section: Mechanism and Postulatesmentioning

confidence: 99%

“…Anti-PD-1 therapy involves blocking the interaction of PD-1 with its ligands PD-L1 and PD-L2 and removes suppression on T cells, enhancing their proliferation. [1] Thus, both CTLA-4 and PD-1 immune checkpoint pathways regulate activation of T cells and play a key role in preventing autoimmunity. CTLA-4 deficient mice develop spontaneous autoimmune disease in which pronounced proliferation, infiltration, and death within weeks are observed.…”

Section: Mechanism and Postulatesmentioning

confidence: 99%

“…If liver biopsy is performed, it will typically reveal diffuse T cell infiltrates. [1] Neurological syndromes such as peripheral neuropathy, spinal demyelination, and myasthenia gravis have been described. [3] Lymphadenopathy appearing in the middle of a cancer treatment usually leads to conclusions of cancer progression and treatment failure, but a sarcoid-like syndrome with significant adenopathy has been described.…”

Section: Miscellaneousmentioning

confidence: 99%

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Unforeseen consequences of cancer immunotherapy

Vaishnav¹,

Arslan²,

Mehta³

2018

Int J Mol Immuno Oncol.

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<p>With the increasing use of immunotherapy for various cancers, it is essential that clinicians become aware of some of the unique consequences and sude effects associated with these new treatments. Ranging from pneumonitis and colitis to Type 1 Diabetes Mellitus, immune related adverse events have been reported. Some side effects may be confused with cancer progression and thus awareness and clinical presentation of these is critical and necessary in this fast moving field of medicine.</p>

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Is autoimmunity the Achilles' heel of cancer immunotherapy?

Cited by 388 publications

References 106 publications

Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities

Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities

Treatment of mycophenolate-resistant immune-related organizing pneumonia with infliximab

Unforeseen consequences of cancer immunotherapy

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