Success and failure of additional immunosuppressants in steroid-refractory pneumonitis related to immune checkpoint blockade.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3078-3078
Author(s):  
Jason Beattie ◽  
Paige Fuentes ◽  
Hira Rizvi ◽  
Jia Luo ◽  
Adam Jacob Schoenfeld ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Immune Checkpoint ◽  
Management Strategies ◽  
Initial Response ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Limited Data ◽  
Tnf Antagonists ◽  
Grade 3 ◽  
Steroid Refractory

3078 Background: Severe immune related adverse events (irAEs) with immune checkpoint blockade are uncommon but can be fatal. Steroids are the most common initial treatment for most non-endocrine irAEs, but some patients are or become refractory to steroids. When steroids are not effective, there is limited data to guide management strategies, particularly in the context of pneumonitis. Methods: All patients at MSK treated with immune checkpoint blockade from 2013-2020 were queried for receipt of an immunosuppressant (e.g. TNF antagonists, mycophenolate mofetil, cyclophosphamide) beyond steroids. Patient records were then manually reviewed to identify patients who received such therapy for management of immunotherapy-related pneumonitis. Results: Among 5363 patients treated with immune checkpoint blockade, 364 (6.8%) received an additional immunosuppressant for an irAE, including 28 (0.5% of all patients treated) patients treated for pneumonitis. Most of these pneumonitis events (19/28, 68%) were grade 3 or higher. Agents used included mycophenolate mofetil (7/28; 25%), TNF antagonists (23/28; 82%), and cyclophosphamide (1/28; 3.5%); more than one medication was used in 3 patients (11%). The indications were primary non-response to steroids (n = 16, 57%) and recrudescence after initial response to steroids (n = 12, 43%). At 90 days from initiation of the additional immunosuppressant, 13/28 (46%) patients were alive with improvement or resolution of pneumonitis while 15/28 (54%) had died. Survival with resolution/improvement was more common in patients treated for recrudescence vs primary non-response (67% vs 25%, p = 0.05). Conclusions: Outcomes with additional immunosuppressants in the setting of steroid-refractory immune-related pneumonitis are poor, but resolution can occur in some cases. A deeper understanding of the mechanistic underpinnings of irAEs is needed to more effectively tailor immunosuppressant therapies, particularly in severe pneumonitis events.

scholarly journals Success and failure of additional immune modulators in steroid-refractory/resistant pneumonitis related to immune checkpoint blockade

2021 ◽  
Vol 9 (2) ◽  
pp. e001884
Author(s):  
Jason Beattie ◽  
Hira Rizvi ◽  
Paige Fuentes ◽  
Jia Luo ◽  
Adam Schoenfeld ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Modulation ◽  
Treatment Strategies ◽  
High Volume ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cancer Center ◽  
Necrosis Factor Alpha ◽  
Immune Modulators ◽  
Steroid Refractory

BackgroundPneumonitis related to immune checkpoint blockade is uncommon but can be severe, fatal or chronic. Steroids are first-line treatment, however, some patients are refractory or become resistant to steroids. Like many immune-related adverse events, little is known regarding the outcomes and optimal management of patients in whom steroids are ineffective.MethodsWe performed a single-center retrospective cohort study at a high-volume tertiary cancer center to evaluate the clinical course, management strategies and outcomes of patients treated for immune checkpoint pneumonitis with immune modulatory medications in addition to systemic steroids. Pharmacy records were queried for patients treated with both immune checkpoint blockade and receipt of additional immune modulators. Records were then manually reviewed to identify patients who received the additional immune modulators for immune checkpoint pneumonitis.ResultsFrom 2013 to 2020, we identified 26 patients treated for immune checkpoint pneumonitis with additional immune modulators in addition to steroids. Twelve patients (46%) were steroid-refractory and 14 (54%) were steroid-resistant. Pneumonitis severity included grade 2 (42%) or grade 3–4 (58%). Additional immune modulation consisted of tumor necrosis factor-alpha inhibitor (77%) and/or mycophenolate (23%). Durable improvement in pneumonitis following initiation of additional immune modulators occurred in 10 patients (38%), including three patients (12%) in whom pneumonitis resolved and all immunosuppressants ceased. The rate of 90-day all-cause mortality/hospice referral was 50%. At last follow-up, mortality attributable to pneumonitis was 23%. In addition to mortality from pneumonitis and cancer, 3 patients (12%) died due to infections possibly associated with immunosuppression.ConclusionsSteroid-refractory or -resistant immune checkpoint pneumonitis is uncommon but associated with significant morbidity and mortality. Additional immunomodulators can yield durable improvement, attained in over one third of patients. An improved understanding of the underlying biology of immune-related pneumonitis will be crucial to guide more precise and effective treatment strategies in the future.

scholarly journals Therapeutic KRASG12C inhibition drives effective interferon-mediated anti-tumour immunity in immunogenic lung cancers

2021 ◽  
Author(s):  
Edurne Mugarza ◽  
Febe van Maldegem ◽  
Jesse Boumelha ◽  
Christopher Moore ◽  
Sareena Rana ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Cytotoxic T Cells ◽  
Initial Response ◽  
Therapeutic Benefit ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Acquired Drug Resistance ◽  
Tumour Immunity ◽  
Pathway Gene

The recent development and approval of KRASG12C inhibitors promises to change profoundly the clinical management of lung cancer patients harbouring KRASG12C mutations. However, early clinical data indicate that acquired drug resistance can frequently develop after the initial response. Due to the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, targeted KRASG12C inhibition can indirectly affect anti-tumour immunity. This has served as a rationale for combination with immune checkpoint blockade, showing therapeutic benefit in certain immunogenic pre-clinical tumour models. In this study, we characterised how KRASG12C inhibition reverses immune suppression driven by oncogenic KRAS in a number of pre-clinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRASG12C inhibition upregulates interferon pathway gene expression via inhibition of Myc and, in tumours, leads to reduced infiltration of immunosuppressive cells, increased interferon responses and antigen presentation, and also enhanced infiltration and activation of cytotoxic T cells. However, the combination of KRASG12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumour model, with KRASG12C inhibition failing to sensitize cold tumours to immunotherapy. In immunogenic tumours, complete responses to KRASG12C inhibition requires tumour cell autonomous interferon gamma signaling. Our data have important implications for the design of clinical trials combining KRASG12C inhibitors with anti-PD-1 drugs and suggest that additional combination strategies will be needed for immunotherapy refractory patients.

Analysis of Advanced Melanomas Changed from Immune Checkpoint Blockade Therapy to Palliative Care

2018 ◽  
Vol 80 (1) ◽  
pp. 51-55
Author(s):  
Ai KAJITA ◽  
Osamu YAMASAKI ◽  
Tatsuya KAJI ◽  
Hiroshi UMEMURA ◽  
Keiji IWATSUKI
Keyword(s):  
Palliative Care ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

Potential immunotherapy for Alzheimer disease and age-related dementia

2019 ◽  
Vol 21 (1) ◽  
pp. 21-25 ◽  
Keyword(s):  
Immune System ◽  
Alzheimer Disease ◽  
Cross Talk ◽  
Immune Checkpoint ◽  
Short Review ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Approach ◽  
Age Related ◽  
The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain's pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain's disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

Potential immunotherapy for Alzheimer disease and age-related dementia

2019 ◽  
Vol 21 (1) ◽  
pp. 21-25 ◽  
Keyword(s):  
Immune System ◽  
Alzheimer Disease ◽  
Cross Talk ◽  
Immune Checkpoint ◽  
Short Review ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Approach ◽  
Age Related ◽  
The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain’s pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain’s disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

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