Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm

Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

The described features may help reveal the immunopathology of similar conditions, including immune-related adverse events and cytokine release syndrome from other immunotherapies or COVID-19, and may inform how long and what type of clinical and immune monitoring is needed.

“We believe that the features described herein may help to identify the immunopathology of similar illnesses, such as irAEs and CRS due to other immunotherapies (e.g. checkpoint inhibitors, CAR-T-cells) or COVID-19 [4, 18, 19], and to inform discussions on the type and length of clinical and immune monitoring warranted in such patients.”

• cites [4] Postow MA, Sidlow R, Hellmann MD (2018) Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 378:158–168. https://doi.org/10.1056/NEJMra1703481 sourceNot checked — no full text of the source
• cites [18] Chua RL, Lukassen S, Trump S et al (2020) COVID-19 severity correlates with airway epithelium-immune cell interaction identified by single-cell analysis. Nat Biotechnol. https://doi.org/10.1038/s41587-020-0602-4 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [19] Kuri-Cervantes L, Pampena MB, Meng W et al (2020) Comprehensive mapping of immune perturbations associated with severe COVID-19. Sci Immunol. https://doi.org/10.1126/sciimmunol.abd7114 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In some cancer patients, immune checkpoint blockade produces immune-related adverse events during short-term follow-up, but reliable immune biomarkers for these effects remain under study.

“Immune checkpoint blockade induces irAEs during short-term follow-up of some patients with cancer, though robust immune biomarkers correlating with adverse effects of therapy are still being investigated [1, 4, 7, 20–25].”

• cites [1] June CH, Warshauer JT, Bluestone JA (2017) Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 23(5):540–547 sourceSupported
• cites [4] Postow MA, Sidlow R, Hellmann MD (2018) Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 378:158–168. https://doi.org/10.1056/NEJMra1703481 sourceNot checked — no full text of the source
• cites [7] Teachey DT, Lacey SF, Shaw PA et al (2016) Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov 6(6):664–679 sourceCould not verify

  The Introduction and Results describe cytokine release syndrome after CAR T-cell therapy, not immune-related adverse events after checkpoint blockade. A search for checkpoint blockade and irAEs found no passage addressing those effects or their biomarkers; the Discussion’s biomarker findings concern CAR T-cell–associated cytokine release syndrome. (LLM, conf=0.79)

  Experimental — accuracy not yet measured
• cites [20] Subudhi SK, Aparicio A, Gao J et al (2016) Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities. Proc Nat Acad Sci 113(42):11919–11924 sourceSupported
• cites [21] Hartmann FJ, Babdor J, Gherardini PF et al (2019) Comprehensive immune monitoring of clinical trials to advance human immunotherapy. Cell Reports 28(3):P819–831.e4 sourceCould not verify

  The Introduction discusses checkpoint blockade as a cancer treatment, and the Results discuss immune signatures associated with graft-versus-host disease after bone marrow transplantation (pages not provided). Searches for immune-related adverse events, short-term follow-up, and biomarkers of checkpoint-blockade adverse effects found no passage addressing the claim. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [22] Oh DY, Cham J, Zhang L et al (2017) Immune toxicities elicited by CTLA-4 blockade in cancer patients are associated with early diversification of the T-cell repertoire. Cancer Res 77(6):1322–1330 sourceSupported
• cites [23] Hegde PS, Karanikas V, Evers S (2016) The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res 22(8):1865–1874. https://doi.org/10.1158/1078-0432.CCR-15-1507 sourceNot checked — no full text of the source
• cites [24] Weide B, Di Giacomo AM, Fonsatti E, Zitvogel L (2015) Immunologic correlates in the course of treatment with immunomodulating antibodies. Semin Oncol 42(3):448–458. https://doi.org/10.1053/j.seminoncol.2015.02.016 sourceNot checked — no full text of the source
• cites [25] Lim SY, Lee JH, Gide TN et al (2019) Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1-based immunotherapy. Clin Cancer Res 25(5):1557–1563. https://doi.org/10.1158/1078-0432.CCR-18-2795 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Cytokine release syndrome and neurotoxicity are the most serious immune-related adverse events, and they are most prominently reported in patients given CAR-T cells.

“The most severe of these immune-related adverse events (irAEs) are cytokine release syndrome (CRS) and neurotoxicity, most prominently described in patients treated with CAR-T-cells [6–11].”

• cites [6] Lee DW, Gardner R, Porter DL et al (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188–195 sourceNot checked — no full text of the source
• cites [7] Teachey DT, Lacey SF, Shaw PA et al (2016) Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov 6(6):664–679 sourcePartly supported

  The Introduction calls CRS the most common potentially severe toxicity associated with CAR T cells, and the Results report encephalopathy in some children with severe CRS. The paper does not identify neurotoxicity as a separate one of the most severe immune-related adverse events or establish that these two events are most prominently reported with CAR-T cells compared with other treatments. The Introduction notes that CRS also occurs with other T-cell-engaging therapies. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [8] Santomasso BD, Park JH, Salloum D et al (2018) Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov 8:958–971 sourceSupported
• cites [9] Wick W, Hertenstein A, Platten M (2016) Neurological sequelae of cancer immunotherapies and targeted therapies. Lancet Oncol 16:e529–e541. https://doi.org/10.1016/S1470-2045(16)30571-X sourceNot checked — no full text of the source
• cites [10] Cuzzubbo S, Javeri F, Tissier M et al (2017) Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur J Cancer 73:1–8. https://doi.org/10.1016/j.ejca.2016.12.001 sourceNot checked — no full text of the source
• cites [11] Gust J, Hay KA, Hanafi L-A et al (2017) Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov 7(12):1404–1419. https://doi.org/10.1158/2159-8290.CD-17-0698 sourcePartly supported

  The Introduction (page unavailable) says CRS develops in most patients after CD19 CAR-T infusion and neurologic adverse events are frequent and can be fatal. The Results report fatal neurotoxicity in four patients. The paper does not establish that these are the most severe immune-related adverse events overall or that they are reported more prominently with CAR-T cells than with other treatments. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

TGN1412 recognized the C''D loop of CD28 and was able to stimulate T-cells through CD28 alone, without the normal T-cell receptor signal.

“The antibody had specificity for the C’’D loop of the CD28 glycoprotein and had the unique capacity to activate T-cells solely through CD28 (signal 2) without the usual ligation of the T-cell receptor (signal 1) [27].”

• cites [27] Beyersdorf N, Gaupp S, Balbach K et al (2005) Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. J Exp Med 202(3):445–455 sourcePartly supported

  The Abstract says CD28 superagonistic antibodies can expand T cells without TCR engagement. The cited paper does not identify TGN1412 or state that it binds the C’’D loop, so it supports the general activation mechanism but not those antibody-specific details. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Immune monitoring is not standard practice for long-term survivors after immunotherapy or cytokine release syndrome, although these patients may still experience late effects and immune-related adverse events.

“For long-term survivors who received immunotherapy or following CRS, immune monitoring is not yet standard of care, despite evidence that such patients may continue to experience secondary effects of treatment and irAEs [1, 3].”

• cites [1] June CH, Warshauer JT, Bluestone JA (2017) Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 23(5):540–547 sourcePartly supported

  The opening discussion (page not supplied) says cancer trials typically follow patients for only about six months and that immunotoxicity can have delayed onset. “Efforts to predict and understand toxicity” (page not supplied) calls for better long-term tracking of irAEs. These passages support concern about late effects, but do not establish that immune monitoring is not standard of care for long-term survivors or for patients following cytokine release syndrome. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [3] Kanjanapan Y, Day D, Butler MO et al (2019) Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials. Eur J Cancer 107:1–7. https://doi.org/10.1016/j.ejca.2018.10.017 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Therapy for cytokine release syndrome and its neurological toxicity chiefly targets IL-6, which probably originates from monocytes or activated endothelial cells.

“Treatment for CRS and associated neurotoxicity primarily targets IL-6, likely arising from monocytes or activated endothelium [1, 6, 11–17].”

• cites [1] June CH, Warshauer JT, Bluestone JA (2017) Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 23(5):540–547 sourceCould not verify

  The ‘Emerging strategies to limit toxicity’ section discusses manipulating cytokine effects to modulate immunotoxicity, but does not say that treatment for CRS and associated neurotoxicity primarily targets IL-6. Searches for IL-6 treatment, monocytes, and activated endothelium found no passage in our copy establishing the claimed treatment or source of IL-6; the ‘Autoimmune consequences’ section mentions IL-6 only in a different context. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites [6] Lee DW, Gardner R, Porter DL et al (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188–195 sourceNot checked — no full text of the source
• cites [11] Gust J, Hay KA, Hanafi L-A et al (2017) Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov 7(12):1404–1419. https://doi.org/10.1158/2159-8290.CD-17-0698 sourcePartly supported

  The Discussion (page unavailable) says treatment of established neurotoxicity has largely included controlling IL-6-mediated inflammatory pathways with tocilizumab as part of CRS management. It does not identify monocytes or activated endothelial cells as the likely source of IL-6; the Results instead show that stimulated brain pericytes secrete IL-6. The Discussion also cautions that targeting IL-6R alone did not prevent neurotoxicity in some patients. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [12] Giavridis T, van der Stegen SJC, Eyquem J et al (2018) CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med 24:731–738 sourcePartly supported

  The paper’s main text (indexed under Abstract; page unavailable) says CRS may respond to IL-6 receptor blockade and identifies recipient macrophages as the main overall source of IL-6, while also finding IL-6 transcripts in monocytes. It does not establish activated endothelial cells as an IL-6 source or say that treatment of associated neurotoxicity primarily targets IL-6; instead, it discusses IL-1 blockade as a potential way to reduce neurotoxicity. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [13] Norelli M, Camisa B, Barbiera G et al (2018) Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med 24(6):739–748. https://doi.org/10.1038/s41591-018-0036-4 sourceNot checked — no full text of the source
• cites [14] Liu Y, Fang Y, Chen X et al (2020) Gasdermin E–mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci Immunol. https://doi.org/10.1126/sciimmunol.aax7969 sourceNot checked — no full text of the source
• cites [15] Staedtke V, Bai R, Kim K et al (2018) Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome. Nature 564:273–277. https://doi.org/10.1038/s41586-018-0774-y sourcePartly supported

  The paper reports testing IL-6 receptor blockade for CRS in mice, with a significant but marginal survival benefit, and identifies IL-6 among myeloid-derived cytokines (main text, labelled Abstract in our copy; page unavailable). It does not establish that treatment for CRS and associated neurotoxicity primarily targets IL-6, or that activated endothelium is a likely source of IL-6. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [16] Agarwal S, June CH (2020) Harnessing CAR T cell insights to develop treatments for hyperinflammatory responses in COVID-19 patients. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-20-0473 sourcePartly supported

  The section on cytokine release in SARS-CoV-2 infection says IL-6 signaling is central to CAR T-cell–associated CRS and that IL-6 or IL-6R blockade can prevent life-threatening complications. The figure caption in the Conclusion attributes IL-6 secretion to macrophages. Our copy does not address treatment of associated neurotoxicity or identify activated endothelial cells as an IL-6 source; page numbers are unavailable. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [17] Hay KA, Hanafi L-A, Li D et al (2017) Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor–modified T-cell therapy. Blood 130(21):2295–2306 sourcePartly supported

  The incidence and kinetics of CRS and neurotoxicity section reports treating patients with tocilizumab and/or dexamethasone, and the Discussion describes these as widely used approaches for severe CRS. The Discussion also reports elevated IL-6 in severe CRS, but it does not identify monocytes or activated endothelium as its source; instead, it discusses IL-6 as a possible contributor to endothelial activation. Page numbers were not available in our copy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Not yet classified.

Autoimmune colitis, vitiligo, and autoantibody production are now included in CTCAE grading of immune-related adverse events due to immunotherapy.

“Autoimmune colitis, vitiligo, and autoantibody production are now included in CTCAE grading of irAEs due to immunotherapy [1, 4, 6, 20, 22, 34].”

• cites [1] June CH, Warshauer JT, Bluestone JA (2017) Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 23(5):540–547 sourcePartly supported

  The section on efforts to predict and understand toxicity describes vitiligo and colitis following immunotherapy. The autoimmune consequences section discusses autoantibodies, but not their production as a graded adverse event. Neither section establishes that these conditions are included in CTCAE grading. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [4] Postow MA, Sidlow R, Hellmann MD (2018) Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 378:158–168. https://doi.org/10.1056/NEJMra1703481 sourceNot checked — no full text of the source
• cites [6] Lee DW, Gardner R, Porter DL et al (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188–195 sourceNot checked — no full text of the source
• cites [20] Subudhi SK, Aparicio A, Gao J et al (2016) Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities. Proc Nat Acad Sci 113(42):11919–11924 sourcePartly supported

  The Results (Table S3; page unavailable) list colitis/diarrhea among graded adverse events related to the study drugs, and the Discussion identifies it as a common immune-related adverse event. The paper does not say that vitiligo or autoantibody production are included, or identify CTCAE as the grading system or discuss a change in what it includes. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [22] Oh DY, Cham J, Zhang L et al (2017) Immune toxicities elicited by CTLA-4 blockade in cancer patients are associated with early diversification of the T-cell repertoire. Cancer Res 77(6):1322–1330 sourcePartly supported

  The Introduction identifies colitis as an immune-related adverse event of checkpoint therapy, and the Results discuss grading adverse events. Neither section establishes that colitis, vitiligo, and autoantibody production are included in CTCAE grading; searches for CTCAE, vitiligo, and autoantibodies found no such passage in our copy. Page numbers were unavailable. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [34] Beck K, Blansfield J, Tran K et al (2006) Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 24(15):2283–2289 sourcePartly supported

  The Abstract and Other Immune Mediated Toxicities section report grade 3/4 enterocolitis after ipilimumab treatment, supporting the colitis portion of the claim. Our copy does not establish that colitis, vitiligo, or autoantibody production are included in CTCAE grading; searches for CTCAE, vitiligo, and autoantibodies did not find that point. Page numbers were not available in the indexed passages. (LLM, conf=0.79)

  Experimental — accuracy not yet measured

May combine two claims.

These observations suggest a role for Th17-cells following TGN1412-induced CRS, and are consistent with other reports of irAEs due to immunotherapy.

“These observations suggest a role for Th17-cells following TGN1412-induced CRS, and are consistent with other reports of irAEs due to immunotherapy [23, 35, 36].”

• cites [23] Hegde PS, Karanikas V, Evers S (2016) The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res 22(8):1865–1874. https://doi.org/10.1158/1078-0432.CCR-15-1507 sourceNot checked — no full text of the source
• cites [35] Volpe E, Sevant N, Zollinger R et al (2008) A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses. Nat Immunol 9(6):650–657 sourceNot checked — no full text of the source
• cites [36] Stummvoll G, DiPaolo R, Huter E et al (2008) Th1, Th2, and Th17 effector T cell-induced autoimmune gastitis differs in pathological pattern and in susceptibility to suppression by regulatory T cells. J Immunol 181:1908–1916 sourcePartly supported

  The Results section ('In vitro differentiated Th1, Th2 and Th17 effectors induce AIG'; page not provided) shows that transferred Th17 cells induced autoimmune gastritis in mice, supporting a general role for Th17 cells in inflammatory disease. The paper does not study TGN1412-induced cytokine release syndrome or report immune-related adverse events caused by immunotherapy, so it cannot support those specific comparisons. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Since the patients are adults, the increase in naïve CD8+ T-cells over 2 years may suggest thymic-independent recovery or the generation of a stable CD45RA+ memory cell subset from the CD45RO+ pool, also described in patients receiving checkpoint blockade.

“Since the patients are adults, the increase in naïve CD8+ T-cells over 2 years may suggest thymic-independent recovery [39], or the generation of a stable CD45RA+ memory cell subset from the CD45RO+ pool [43], also described in patients receiving checkpoint blockade [24].”

• cites [39] Mackall C, Fleisher T, Brown M et al (1997) Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy. Blood 89(10):3700–3707 sourceNot checked — no full text of the source
• cites [43] Faint J, Annels N, Curnow S et al (2001) Memory T cells constitute a subset of the human CD8+CD45RA+ pool with distinct phenotypic and migratory characteristics. J Immunol 167:212–220 sourceSupported
• cites [24] Weide B, Di Giacomo AM, Fonsatti E, Zitvogel L (2015) Immunologic correlates in the course of treatment with immunomodulating antibodies. Semin Oncol 42(3):448–458. https://doi.org/10.1053/j.seminoncol.2015.02.016 sourceNot checked — no full text of the source

May combine two claims.

This cytokine rise coincided with a decline in serum erythropoietin and, given similar hemoglobin levels and renal function to other patients, may indicate that erythropoietin was immunomodulatory in this setting.

“This cytokine rise coincided with the decline in serum erythropoietin and, in the setting of hemoglobin levels and renal function similar to those of the other patients, may have indicated that erythropoietin was immunomodulatory in this setting [37, 38].”

• cites [37] Shang Y, Li X, Prasad P et al (2009) Erythropoietin attenuates lung injury in lipopolysaccharide treated rats. J Surgical Res 155:104–110 sourceNot checked — no full text of the source
• cites [38] Yuan R, Maeda Y, Li W et al (2008) Erythropoietin: a potent induces of peripheral immuno/inflammatory modulation in autoimmune EAE. PLoS ONE 3(4):e1924 sourcePartly supported

  The Results section reports that EPO treatment reduced pro-inflammatory cytokines in EAE T-cell cultures, supporting the possibility that EPO is immunomodulatory. The paper does not report the cited patients’ decline in serum erythropoietin, coincident cytokine rise, or comparisons of hemoglobin levels and renal function; its findings therefore do not establish that interpretation in the patients’ setting. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S2 (checkable).

Clinical-pathologic correlation in these individuals resulted in valuable observations that may be instructive in understanding mechanisms of immune-induced pathologies, including those of checkpoint inhibitors, CAR-T cells, and infections such as COVID-19.

“Clinical–pathologic correlation in these individuals resulted in valuable observations that may be instructive in understanding mechanisms of immune-induced pathologies, including those of checkpoint inhibitors, CAR-T cells, and infections such as COVID-19, known to target mucosal tissues and cause severe CRS [1, 5, 8, 18, 19].”

• cites [1] June CH, Warshauer JT, Bluestone JA (2017) Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 23(5):540–547 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [5] Cousin S, Italiano A (2016) Molecular pathways: immune checkpoint antibodies and their toxicities. Clin Cancer Res 22(18):4550–4555 sourceNot checked — no full text of the source
• cites [8] Santomasso BD, Park JH, Salloum D et al (2018) Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov 8:958–971 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [18] Chua RL, Lukassen S, Trump S et al (2020) COVID-19 severity correlates with airway epithelium-immune cell interaction identified by single-cell analysis. Nat Biotechnol. https://doi.org/10.1038/s41587-020-0602-4 sourceSupported
• cites [19] Kuri-Cervantes L, Pampena MB, Meng W et al (2020) Comprehensive mapping of immune perturbations associated with severe COVID-19. Sci Immunol. https://doi.org/10.1126/sciimmunol.abd7114 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Not yet classified.

Dendritic cells were undetectable at first and returned to normal numbers within one month.

“Dendritic cells, initially undetectable, rose to normal within a month.”

• AssumptionRests on an assumption: The healthy control volunteers were comparable to the patients in baseline immune status apart from TGN1412 exposure.

May combine two claims.

Intermittent mild neutropenia and autoantibody production were observed in the patients.

“Mild neutropenia and autoantibody production was observed intermittently.”

May combine two claims.

One patient developed peripheral dry gangrene, underwent amputations, and had ongoing Raynaud's phenomenon.

“One patient suffered from peripheral dry gangrene, required amputations, and had persistent Raynaud’s phenomenon.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

One patient had pruritus with raised IgE, and raised IgE was also detected in three other patients who had no symptoms.

“One had pruritus associated with elevated IgE levels, also found in three other asymptomatic patients.”

May combine two claims.

Two of the patients with depression, both of whom had needed prolonged intensive care, also met criteria for post-traumatic stress disorder; one of these additionally had panic disorder and agoraphobia.

“two of these, who required a prolonged stay in intensive care, were also diagnosed with post-traumatic stress disorder, (one also had associated panic disorder and agoraphobia; Table 1)”

May combine two claims.

Dysfunction across cognitive, psychological, gastrointestinal, integumentary, and immune regulatory systems continued for years after the TGN1412 event.

“All patients survived; dysfunction in cognitive, psychological, gastrointestinal, integumentary, and immune regulatory systems persisted for years following the event.”

May combine two claims.

Naïve CD8+ T-cells stayed at high levels, while naïve CD4+ and memory CD4+ and CD8+ T-cells began high and then decreased over two years.

“Naïve CD8+ T-cells were maintained at high levels, whereas naïve CD4+ and memory CD4+ and CD8+ T-cells started high but declined over 2 years.”

• AssumptionRests on an assumption: The healthy control volunteers were comparable to the patients in baseline immune status apart from TGN1412 exposure.

May combine two claims.

Longer-term effects after TGN1412 exposure affected every patient in four domains: cognitive and psychiatric, autoimmune and inflammatory, immune mucosal barrier function, and changes in immune cell subsets and cytokines in peripheral blood.

“Longer term effects following exposure to TGN1412 affected all patients in four main areas: cognitive and psychiatric, autoimmune and inflammatory, immune mucosal barrier function, and alterations in immune cell subsets and cytokines in peripheral whole blood (Table 1; Supplementary Fig. 3).”

• AssumptionRests on an assumption: The long-term clinical and immunological abnormalities seen in the six patients were caused by TGN1412 exposure rather than by other factors.

May combine two claims.

T-regulatory cells showed a circannual cycle and their numbers were normal.

“T-regulatory cells cycled circannually and were normal in number.”

• AssumptionRests on an assumption: The healthy control volunteers were comparable to the patients in baseline immune status apart from TGN1412 exposure.

May combine two claims.

After the first 5 months, naïve CD8+ T-cells persisted above normal while naïve CD4+ T-cells gradually declined.

“Thereafter, naïve CD8+ T-cells persisted above normal and naïve CD4+ T-cells gradually declined (Fig. 3, Supplementary Fig. 4–6, c&d).”

May combine two claims.

Three other patients (D, E, F) also had persistently elevated IgE without specific symptoms or seasonal correlation; two of them (E, F) also showed mild eosinophilia.

“Three other patients (D, E, F) also had persistently elevated IgE, without specific symptoms or seasonal correlation, two of whom also showed mild eosinophilia (E, F; Fig. 1b,c).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The headaches were sharp, short-lasting, severe, and often localized to the vertex of the head.

“The headaches were sharp, short-lasting and severe, often affecting the vertex of the head.”

Not yet classified.

Patient B had mild dry eyes and blepharitis with hypermetropia.

“Patient B had mild dry eyes and blepharitis with hypermetropia.”

Not yet classified.

Naïve CD4+ and CD8+ T-cells were detectable in low-to-normal range with a cyclical recovery pattern to normal over the first 5 months.

“Naïve CD4+ and CD8+ T-cells were detectable in low-to-normal range with a cyclical recovery pattern to normal over the first 5 months.”

May combine two claims.

Autoimmune antibody testing in patient D was consistently negative except for weak ANA (1:40 speckled) at 7 and 8 months and low-titer anti-cardiolipin IgG at 8 and 24 months.

“Autoimmune antibody testing was consistently negative in this patient except for expression of a weak anti-nuclear antibody (ANA; 1:40 titer) in speckled pattern at 7 and 8 months and a low-titer anti-cardiolipin IgG antibody at 8 and 24 months following infusion.”

May combine two claims.

The cognitive changes and the serious adverse event caused significant anxiety, and four patients needed psychotherapy.

“These changes, in addition to the SAE itself, generated significant anxiety; psychotherapy was required in four (Table 1).”

Not yet classified.

Three of these lumps were biopsied on two occasions 14 months apart and were found to be benign lipomas or angiolipomas.

“Three of these lumps were biopsied on two occasions, 14 months apart and were found to be benign lipomas or angiolipomas.”

May combine two claims.

Memory CD4+ and CD8+ T-cells were detected at higher-than-normal values and remained so until 9-12 months post-infusion, followed by a gradual decline in both to subnormal levels.

“Memory CD4+ and CD8+ T-cells were detected at higher-than-normal values and remained so until 9–12 months post-infusion, followed by a gradual decline in both to subnormal levels (Fig. 3, Supplementary Fig. 4–6, e&f).”

May combine two claims.

Patient D's fingers showed decreased pigmentation, and Raynaud's phenomenon was noted in both hands 10 months post-infusion, worsening during winter of the second year (18-24 months).

“The fingers of both hands displayed decreased pigmentation and, 10 months post-infusion, Raynaud’s phenomenon was noted in both hands that worsened during winter of the second year (18–24 months; Table 1).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Mobile, nontender, rubbery subcutaneous lumps were noted on the arms and thorax of patient C.

“Mobile, nontender and rubbery subcutaneous lumps were noted on the arms, and thorax of patient C (Table 1).”

Not yet classified.

Immune cells were not identified in these biopsies, and a CT scan did not show significant adenopathy or lesions elsewhere.

“Immune cells were not identified in these biopsies and a CT scan did not show significant adenopathy or lesions elsewhere.”

May combine two claims.

Five patients experienced intermittent headaches that began several days after stopping steroids on Days +21-31 and became less frequent in the second year.

“Five patients had intermittent headaches that started several days after stopping steroids on Days + 21–31 and became less frequent in the second year (Table 1; Supplementary Fig. 3).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Patient D did not have headaches or blurred vision, yet was the most physically ill, requiring a prolonged ICU stay and prolonged steroids.

“Interestingly, patient D did not have headaches or blurred vision, yet was the most physically ill, requiring a prolonged stay in intensive care and a prolonged course of steroids.”

May combine two claims.

Patient B had ongoing pruritus over all skin areas, and cetirizine could not be discontinued over 2 years due to recurrence of debilitating symptoms.

“Patient B suffered from ongoing pruritus over all skin areas; cetirizine could not be discontinued over 2 years due to recurrence of debilitating symptoms (Table 1 and Supplementary Fig. 3).”

May combine two claims.

These autoantibodies lasted less than 5 months at a time and did not correlate with changes in cell subsets or cytokine measurements.

“These antibodies lasted less than 5 months at a time and did not correlate with changes in cell subsets or cytokine measurements.”

May combine two claims.

Peripheral blood monocytes recovered to normal by Day +10, unrelated to the recovery kinetics of dendritic cells.

“Peripheral blood monocytes had recovered to normal by Day + 10, unrelated to the recovery kinetics of DCs [26].”

• cites [26] Suntharalingam G, Perry M, Ward S et al (2006) Cytokine Storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028 sourceNot checked — no full text of the source

May combine two claims.

A full gastrointestinal work-up in patient B included a normal lactose intolerance test, esophagogastroduodenoscopy, and colonoscopy; a 5 mm sessile polyp in the proximal ascending colon showed inflammatory change.

“Because of the extent of symptoms in patient B, a full gastrointestinal work-up was undertaken including lactose intolerance test (normal), esophagogastroduodenoscopy, and colonoscopy; a 5 mm sessile polyp in the proximal ascending colon showed inflammatory change.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Patients with headaches also had mild blurred distance vision.

“The patients with headaches also had mild blurred distance vision (Table 1);”

Not yet classified.

Patient D was the most physically ill after TGN1412 infusion and had ischemic hands and feet of unclear cause.

“Patient D was the most physically ill following TGN1412 infusion and suffered ischemic hands and feet of unclear cause (Table 1; Fig. 2a,b).”

Not yet classified.

In four patients, arthralgias were associated with low-titer autoantibodies: ANA (patient D), ACA (patients A, D, E, F), intermittent equivocal RF (patient A), or positive ANCA in perinuclear pattern against PR3 (patient A, who also had mild neutropenia).

“In four, symptoms were associated with low-titer anti-nuclear antibody (ANA; patient D), anti-cardiolipin antibody (ACA; patients A, D, E, F), intermittent equivocal rheumatoid factor (RF; patient A) or a positive anti-nuclear cytoplasmic antibody (ANCA) in perinuclear staining pattern directed against PR3 (patient A; also displayed mild neutropenia).”

May combine two claims.

Patient B had persistently increased IgE and intermittent mild eosinophilia without other associated signs or symptoms of allergy.

“He had a persistently increased level of IgE, and intermittent mild eosinophilia without other associated signs or symptoms of allergy (Fig. 1b,c).”

May combine two claims.

Patient A, the eldest with the most severe memory and cognitive problems, had a lumbar puncture one year post-event showing oligoclonal bands matched between serum and cerebrospinal fluid.

“The eldest (patient A), whose memory and cognitive problems were most severe, had a lumbar puncture one year post-event which showed oligoclonal bands matched between serum and cerebrospinal fluid.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In patient C, ophthalmologic testing found no retinal disease or intraocular inflammation, but a change in contrast sensitivity was noted; he declined further testing.

“in patient C, whose symptoms were most severe, ophthalmologic testing did not reveal retinal disease or intraocular inflammation, although a change in contrast sensitivity of vision was noted; he declined further testing.”

May combine two claims.

The patients improved at first and then reached a plateau about 12 months after the event.

“The patients initially showed some improvement, plateauing approximately 12 months after the event.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Five patients had normal FDG-PET brain scans, while one patient declined the scan.

“Five patients had normal FDG-PET brain scans (one patient declined).”

May combine two claims.

Comparison of intracellular CD4+ and CD8+ T-cell cytokines (spontaneous and stimulated IL-4, IL-10, and IFNγ) indicated that patients B and D were similar to each other and different from patients A, C, E, and F (p < 0.001).

“Comparison of intracellular CD4+ and CD8+ T-cell cytokines (spontaneous and stimulated IL-4, IL-10 and IFNγ) indicated that patients B and D were similar to each other and different from patients A, C, E and F (p < 0.001).”

May combine two claims.

Intravenous infusion of TGN1412 resulted in a cytokine storm heralded by high serum TNFα within an hour, with fever, delirium, headache, nausea, vomiting, diarrhea, early and rapidly progressive lung involvement with hypoxemia, and disseminated intravascular coagulation.

“Intravenous infusion of the CD28 superagonist antibody, TGN1412, resulted in a cytokine storm heralded by high serum TNFα levels within an hour of infusion, with fever, delirium, headache, nausea, vomiting and diarrhea, early and rapidly progressive lung involvement with hypoxemia and disseminated intravascular coagulation.”

May combine two claims.

Patient B had a sustained increase in erythropoietin from Day +10 until 3 months, when IFNγ, IL-1β, IL-12p70, IL-8, IL-4, IL-5, and IL-17 all started to increase, with another peak in these cytokines at month nine.

“He had a sustained increase in erythropoietin from Day + 10 following infusion until 3 months when IFNγ, IL-1β, IL-12p70, IL-8, IL-4, IL-5 and IL-17 all started to increase with another peak in these cytokines noted at month nine.”

May combine two claims.

The first headaches in all patients appeared within 90 min of infusion, coincident with delirium and an early rise in TNFα.

“The first headaches in all patients appeared within 90 min of infusion, coincident with delirium and an early rise in TNFα [30, 31].”

• cites [30] Mrak R, Griffin W (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26:349–354 sourceNot checked — no full text of the source
• cites [31] Kipnis J, Derecki N, Yang C, Scrable H (2008) Immunity and cognition: what do age-related dementia, HIV-dementia and "chemo-brain" have in common? Trends Immunol 29(10):455–463 sourceNot checked — no full text of the source

May combine two claims.

Patient B had higher serum IFNγ (p < 0.001) starting from 2.5 months and a different cytokine response in general compared with the other patients (p < 0.001).

“Patient B also had higher serum IFNγ (p < 0.001) starting from 2.5 months, and a different cytokine response in general when compared with that of the other patients (Fig. 4; p < 0.001).”

May combine two claims.

Early peripheral blood depletion of lymphocytes and monocytes was observed with slow and specific recovery kinetics, shared by all affected individuals.

“Early peripheral blood depletion of lymphocytes and monocytes was observed with slow and specific recovery kinetics, shared by all affected individuals [26].”

• cites [26] Suntharalingam G, Perry M, Ward S et al (2006) Cytokine Storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028 sourceNot checked — no full text of the source

Not yet classified.

The first peak of the CD8+ "Treg" subset occurred three months before the CD4+ "Treg" peak, but thereafter they cycled together.

“Interestingly, the first peak of the CD8+ “Treg” subset occurred three months prior to that of the CD4+ “Treg” peak, but thereafter cycled together.”

May combine two claims.

All patients had IL-17 levels during immune reconstitution higher than those of normal controls, and a high level of IgE was found in four patients.

“All patients had IL-17 levels during immune reconstitution higher than those of normal controls, and a high level of IgE was found in four patients.”

May combine two claims.

Patient D, who had several operations and recurrent wound infections during the 2-year follow-up, shared similar cellular and cytokine profiles with patients A and B, respectively.

“Although the clinical relevance of these groupings is currently unclear, it is notable that patient D, who had several operations and recurrent infections of his wounds during the 2-year follow-up, shared similar cellular and cytokine profiles with those of patients A and B, respectively.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Patient B also had worsening of memory and cognitive symptoms and pruritus at month three following TGN1412 infusion.

“He also had a worsening of his memory and cognitive symptoms and pruritus at month three following TGN1412 infusion.”

May combine two claims.

Activated CD4+ and CD8+ T-cells were initially high, returned to normal range over 6 months, and followed the recovery pattern of dendritic cells and the slow decrease of memory T-cells.

“Activated CD4+ and CD8+ T-cells were initially high, returned to normal range over 6 months (Fig. 3, Supplementary Fig. 4–6, i&j) and followed the recovery pattern of DCs and the slow decrease of memory T-cells (Supplementary Fig. 7).”

May combine two claims.

IL-6, IL-17, and TNFα levels in patients A, D, E, and F increased during the last 6 months of monitoring and coincided with declining CD4+/CD45RA+, CD4+/CD45RO+, and CD8+/CD45RO+ T-cell and Treg numbers during this time.

“IL-6, IL-17 and TNFα levels in patients A, D, E and F increased during the last 6 months of monitoring, and coincided with declining CD4+/CD45RA+, CD4+/CD45RO+ and CD8+/CD45RO+ T-cell and Treg numbers during this time.”

May combine two claims.

CD25+/CD28+ T-cell subsets, including CD4+ Tregs and corresponding CD8+ "Treg" population, were in normal range when monitoring started, decreased to low-to-normal over months 1 and 2, and continued to cycle circannually within normal range over the 2-year period.

“The CD25+/CD28+ T-cell subsets, which include the CD4+ Tregs and corresponding CD8+ “Treg” population, were in normal range when monitoring started, decreased to low-to-normal levels over months 1 and 2, and continued to cycle circannually within the normal range over the 2-year period (Fig. 3, Supplementary Fig. 4–6, g&h).”

May combine two claims.

Patients A and D showed different cell subset numbers and longitudinal follow-up compared with the other four patients (p < 0.001), especially low numbers of CD4+ naïve T-cells and "Tregs" over time.

“Patients A and D showed different cell subset numbers and longitudinal follow-up versus those of the other four patients (Fig. 3; p < 0.001), especially regarding low numbers of CD4+ naïve T-cells and “Tregs” over time.”

May combine two claims.

Some of these patients also had psychological difficulties, headaches, autoimmune and mucosal barrier dysregulation, in addition to immune cell subset and cytokine irregularities in peripheral blood.

“Some also had psychological difficulties, headaches, autoimmune and mucosal barrier dysregulation in addition to immune cell subset and cytokine irregularities in peripheral blood.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The work took place in a GLP-compliant laboratory as exploratory research, following established protocols that met MIATA standards.

“These studies were conducted in a laboratory operating under GLP principles, undertaking exploratory research and using established protocols that were MIATA compliant (Supplementary MIATA information).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Every test plate included method controls and normal control samples as well as standard calibration controls.

“Method controls and normal control samples were included on each test plate in addition to standard controls for calibration.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Immunological follow-up ended for patients B and C after 15 and 22 months, respectively.

“Patients B and C were lost to immunological follow-up after 15 and 22 months, respectively.”

May combine two claims.

Pre-clinical work had predicted that T-regulatory cells would expand selectively without cytokine release, yet the initial human response was a cytokine storm.

“Although the expected effect from pre-clinical studies was for selective T-regulatory cell (Treg) expansion, without cytokine release, the first effects observed in humans were those of cytokine storm.”

Classified as probably not a substantial claim.

Only time-points with complete data from all six patients and six controls were analyzed.

“Time-points were only included when data from all six patients and six controls were available.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Each ELISA was run twice and on different plates to control for plate-to-plate variability.

“ELISA determinations were done in duplicate and on different plates to account for plate-to-plate variation.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The second hypothesis did not meet the homogeneity-of-variance assumption, as expected given the small sample size and absence of replicates.

“Due to the small sample size (no replicates), the homogeneity of variance, expectedly, was not satisfied only for the second hypothesis.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Blood samples from patients were anonymized, and laboratory staff running immunological assays were blinded to clinical symptoms, signs, and laboratory results.

“All patient blood samples were anonymized and the scientists performing immunologic tests were not aware of clinical symptoms, signs, or clinical laboratory data (NEM, AJS, HOA-H, CLP, MK, AM and SCK).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The patients had no notable medical history and were all healthy in the two weeks before the trial.

“None of the patients had a notable medical history and all were well during the 2 weeks preceding the clinical trial.”

May combine two claims.

In 2006, six healthy young men received TGN1412, a humanized superagonist antibody against CD28, in a first-in-human trial.

“In 2006, a superagonist anti-CD28 humanized monoclonal antibody (TGN1412) was infused into six healthy young male volunteers in a first-in-man clinical trial [26].”

• cites [26] Suntharalingam G, Perry M, Ward S et al (2006) Cytokine Storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

From Day + 133 onward, patients were assessed on two separate days rather than all six on one day; this produced significant differences in total cell counts for some T-cell subsets compared with earlier analyses, in both patients and healthy controls.

“At this time, patients were evaluated on 2 separate days, rather than all six on 1 day, allowing for faster laboratory processing of samples (with less cell death), but resulting in significant disparity in total cell numbers in certain T-cell subsets versus analyses prior to Day + 133 for both the patient and healthy-control samples.”

May combine two claims.

Every volunteer developed cytokine release syndrome, with the first clinical signs appearing within 90 minutes after infusion.

“All six volunteers suffered from CRS, first noted clinically within 90 min of infusion.”

• cites [26] Suntharalingam G, Perry M, Ward S et al (2006) Cytokine Storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The assays and reagents had been validated beforehand and their performance checked during routine general investigative work.

“The assays and reagents employed were previously validated and tested for performance during the course of standard general investigative research.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The healthy controls were men with a median age of 30 years and a range of 19 to 42 years.

“The healthy control volunteers were male, with a median age of 30 years (range 19–42).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Statisticians who were not involved in acquiring the data, except for serum cytokine ELISA measurements, and who were blinded to clinical outcomes carried out the analysis.

“The statistical analysis was performed by scientists (MK, AM) not involved in acquisition of data, except for serum cytokine determinations by ELISA, and without knowledge of clinical outcomes.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

All six participants in the TGN1412 trial were men; their median age was 29.5 years, with a range of 19 to 34 years.

“All six TGN1412 trial participants were male, with median age of 29.5 years (range 19–34).”

May combine two claims.

The TGN1412 cohort consisted of young, healthy individuals who had been extensively screened for a first-in-man clinical trial and received an immune stimulus that resulted in CRS simultaneously.

“In contrast, the significance of the cohort given TGN1412 is that they were all young and healthy, having been screened extensively for a first-in-man clinical trial, and had an immune stimulus that resulted in CRS simultaneously.”

Classified as probably not a substantial claim. May combine two claims.

The patients received similar and concurrent treatment, which enabled monitoring for irAEs and immunological biomarker assessment for clinical-pathologic correlation.

“The patients received similar and concurrent treatment, which enabled monitoring for irAEs and immunological biomarker assessment for clinical–pathologic correlation.”

Probably not a substantial claim: may not pass S3 (load-bearing).

These similarities may indicate potentially common cellular/immune mechanisms underlying different clinical problems in these patients.

“These similarities may indicate potentially common cellular/immune mechanisms underlying different clinical problems found in these patients.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Headache is now a well-described immune-related adverse event.

“although headache is now a well-described irAE [9].”

• cites [9] Wick W, Hertenstein A, Platten M (2016) Neurological sequelae of cancer immunotherapies and targeted therapies. Lancet Oncol 16:e529–e541. https://doi.org/10.1016/S1470-2045(16)30571-X sourceNot checked — no full text of the source

Not yet classified.

The different recovery kinetics of monocytes and dendritic cells are consistent with their distinct lineages.

“It is notable that following the initial disappearance of blood mononuclear cells (coincident with CRS) there were different recovery kinetics of monocytes and DCs, consistent with the distinct lineages of these populations.”