scholarly journals Pneumonitis in Patients Treated With Anti–Programmed Death-1/Programmed Death Ligand 1 Therapy

2017 ◽  
Vol 35 (7) ◽  
pp. 709-717 ◽  
Author(s):  
Jarushka Naidoo ◽  
Xuan Wang ◽  
Kaitlin M. Woo ◽  
Tunc Iyriboz ◽  
Darragh Halpenny ◽  
...  
Keyword(s):  
T Cell ◽  
Cytotoxic T Cell ◽  
Cancer Center ◽  
Low Grade ◽  
Programmed Death Ligand 1 ◽  
Exact Test ◽  
Underlying Malignancy ◽  
Programmed Death ◽  
Pathologic Features ◽  
Programmed Death 1

Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti–programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. Methods Patients who received anti–PD-1/PD-L1 monotherapy or in combination with anti–cytotoxic T-cell lymphocyte associated antigen-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher’s exact test as were associations between pneumonitis features and outcomes. Results Of 915 patients who received anti–PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P < .01). Incidence was similar in patients with melanoma and non–small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [ P = 1.0]; combination, 11 of 115 v four of 57 [ P = .78]). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion Pneumonitis associated with anti–PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti–PD-1/PD-L1 mAbs are combined with anti–cytotoxic T-cell lymphocyte associated antigen-4 mAb. Most events are low grade and improve/resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.

scholarly journals Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Khashayar Esfahani ◽  
Tho-Alfakar Al-Aubodah ◽  
Pamela Thebault ◽  
Réjean Lapointe ◽  
Marie Hudson ◽  
...  
Keyword(s):  
T Cell ◽  
Elevated Serum ◽  
Cytotoxic T Cell ◽  
Solid Organ ◽  
Organ Rejection ◽  
Cell Numbers ◽  
Cell Responses ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Ifn Γ

Abstract Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)-γ+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ+ CD4+ T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.

scholarly journals Immunophenotype of T Cells Expressing Programmed Death-1 and Cytotoxic T Cell Antigen-4 in Early Lung Cancer: Local vs. Systemic Immune Response

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 567 ◽  
Author(s):  
Iwona Kwiecien ◽  
Tomasz Skirecki ◽  
Małgorzata Polubiec-Kownacka ◽  
Agata Raniszewska ◽  
Joanna Domagala-Kulawik
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Local Environment ◽  
Lavage Fluid ◽  
Cytotoxic T Cell ◽  
Multiparameter Flow Cytometry ◽  
Cell Antigen ◽  
Programmed Death ◽  
Programmed Death 1

The overexpression of programmed death-1 (PD-1) and cytotoxic T cell antigen 4 (CTLA-4) receptors on T cells are among the major mechanisms of tumor immunoevasion. However, the expression pattern of these receptors on T cell subpopulations of a different activation status and at different sites is poorly characterized. Thus, we analyzed the expression of PD-1 and CTLA-4 on the naïve, activated, memory, and activated memory T cells. Bronchoalveolar lavage fluid (BALF) from the lung affected by lung cancer (clBALF), the opposite ‘healthy’ lung (hlBALF), and peripheral blood (PB) samples were collected from 32 patients. The cells were analyzed by multiparameter flow cytometry. The proportion of memory, activated, and activated memory CD8+ cells with the expression of PD-1 and CTLA-4 were elevated in the clBALF when compared to the hlBALF (insignificantly), but these proportions were significantly higher in the BALF when compared with the PB. The proportions of PD-1+ and CTLA-4+ T cells were elevated in the squamous cell carcinoma when compared to the adenocarcinoma patients. Also, the expression of PD-1 and CTLA-4 on T cells from the BALF was significantly higher than from PB. We report for the first time the differential expression of checkpoint molecules on CD4+ and CD8+ lymphocytes at a different stage of activation in the local environment of lung cancer. Moreover, the circulating T cells have a distinct expression of these receptors, which suggests their poor utility as biomarkers for immunotherapy.

scholarly journals Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jang-June Park ◽  
Emily P. Thi ◽  
Victor H. Carpio ◽  
Yingzhi Bi ◽  
Andrew G. Cole ◽  
...  
Keyword(s):  
T Cell ◽  
Small Molecule ◽  
Viral Infections ◽  
Checkpoint Inhibition ◽  
Humanized Mouse Model ◽  
Programmed Death Ligand 1 ◽  
Therapeutic Implications ◽  
Cell Responses ◽  
Programmed Death ◽  
Programmed Death 1

AbstractProgrammed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.

Activation of central/effector memory T cells in advanced gastric cancer patients treated with antiprogrammed death-1 antibody.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 54-54 ◽  
Author(s):  
Hirofumi Ohmura ◽  
Kyoko Yamaguchi ◽  
Fumiyasu Hanamura ◽  
Mamoru Ito ◽  
Akitaka Makiyama ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
T Cell ◽  
Advanced Gastric Cancer ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Effector Memory ◽  
Cytotoxic T Cell ◽  
Programmed Death ◽  
Programmed Death 1

54 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances antitumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 (PD-L1) and has shown efficacy for advanced gastric cancer (AGC) in the salvage line. However, specific subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood mononuclear cells of 20 AGC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). The proportion of immune cell subsets were systematically analyzed by flow cytometry, including the expression of costimulatory and coinhibitory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T cell antigen-4 (CTLA-4), CD28, OX40, and inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were analyzed. Results: Median progression free survival (PFS) of the whole patients was 51 days (95% CI 35–83). After a single course of nivolumab, patients showed a significant increase in activated effector memory and activated effector subsets of CD4+/CD8+ T cells (p = 0.018, 0.018, 0.032, 0.024). At the time of PD, proportions of myeloid dendritic cell, IgM memory B cell and Tfh-Th1/17 cell subsets decreased (p = 0.024, 0.013, 0.0039). On the other hand, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells increased at the time of PD (p = 0.013, 0.032, 0.042, 0.042). Significant positive correlations were found between PFS and the proportion of LAG3 positive CD4+/CD8+ T cells (p = 0.0056, 0.0054), OX 40 positive CD4+/CD8+ T cells (p = 0.0034, 0.0006) prior to the initial nivolumab therapy. Conclusions: Nivolumab therapy enhances activation of effector memory and effector subsets of CD4+/CD8+ T cells. The expression level of LAG3 and OX40 on T cells might be correlated with efficacy of nivolumab therapy.

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