Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy

Zimmer, Lisa; Goldinger, Simone M.; Hofmann, Lars; Loquai, Carmen; Ugurel, Selma; Thomas, Ioannis; Schmidgen, Maria Isabel; Gutzmer, Ralf; Utikal, Jochen; Göppner, Daniela; Hassel, Jessica C.; Meier, Friedegund; Tietze, Julia K.; Forschner, Andrea; Weishaupt, Carsten; Leverkus, Martin; Wahl, R.U.; Dietrich, U.; Garbe, Claus; Kirchberger, Michael C.; Eigentler, Thomas; Berking, Carola; Gesierich, Anja; Krackhardt, Angela M.; Schadendorf, Dirk; Schuler, Gerold; Dummer, Reinhard; Heinzerling, Lucie

doi:10.1016/j.ejca.2016.02.024

Cited by 508 publications

(379 citation statements)

References 32 publications

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“…Moreover, this may also induce an indiscriminate reactivation of antigen-experienced T cells, including functionally silenced yet potentially deleterious autoreactive T cells, leading to severe autoimmune-related adverse events during and after treatment. 8 , 12 , 22 …”

Section: Discussionmentioning

confidence: 99%

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

et al. 2018

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PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired antigen-experienced anticancer T cells. However, the efficacy of current PD-L1-blocking antibodies is potentially reduced by ‘on-target/off-tumor’ binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity may induce a generalized activation of all antigen-experienced T cells which may explain the frequent occurrence of autoimmune-related adverse events during and after treatment.To address these issues, we constructed a bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and to more selectively reactivate anticancer T cells. Indeed, the IC50 of PD-L1xEGFR for blocking PD-L1 on EGFR+ cancer cells was ∼140 fold lower compared to that of the analogous PD-L1-blocking bsAb PD-L1xMock with irrelevant target antigen specificity. Importantly, activation status, IFN-γ production, and oncolytic activity of anti-CD3xanti-EpCAM-redirected T cells was enhanced when cocultured with EGFR-expressing carcinoma cells. Similarly, the capacity of PD-L1xEGFR to promote proliferation and IFN-γ production by CMVpp65-directed CD8+ effector T cells was enhanced when cocultured with EGFR-expressing CMVpp65-transfected cancer cells. In contrast, the clinically-used PD-L1-blocking antibody MEDI4736 (durvalumab) promoted T cell activation indiscriminate of EGFR expression on cancer cells. Additionally, in mice xenografted with EGFR-expressing cancer cells 111In-PD-L1xEGFR showed a significantly higher tumor uptake compared to 111In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, thereby promoting the selective reactivation of anticancer T cells. This novel targeted approach may be useful to enhance efficacy and safety of PD-1/PD-L1 checkpoint blockade in EGFR-overexpressing malignancies.

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Section: Discussionmentioning

confidence: 99%

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

et al. 2018

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“…[82][83][84] Fatigue is observed in up to 20% of patients. For endocrine AEs, specific treatment such as hormonal replacement (for hypothyroidism and diabetes mellitus) may be required.…”

Section: Management Of Toxicitiesmentioning

confidence: 99%

Pembrolizumab (Keytruda)

Kwok

Yau

Chiu

et al. 2016

Human Vaccines & Immunotherapeutics

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The programmed cell death protein 1 (PD1) is one of the checkpoints that regulates the immune response. Ligation of PD1 with its ligands PDL1 and PDL2 results in transduction of negative signals to T-cells. PD1 expression is an important mechanism contributing to the exhausted effector T-cell phenotype. The expression of PD1 on effector T-cells and PDL1 on neoplastic cells enables tumor cells to evade anti-tumor immunity. Blockade of PD1 is an important immunotherapeutic strategy for cancers. Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD1 antibody that has been extensively investigated in numerous malignancies. In melanoma refractory to targeted therapy, pembrolizumab induced overall response rates (ORRs) of 21-34%. It was superior to another immune checkpoint inhibitor ipilimumab (Yervoy) in stage III/IV unresectable melanoma. In refractory non-small cell lung cancer (NSCLC), pembrolizumab induced ORRs of 19-25%. Based on these results, pembrolizumab was approved by the USA FDA for the treatment of advanced melanoma and NSCLC. Tumor cell PDL1 expression may be a valid response predictor. Molecular analysis also showed that tumors with high gene mutation burdens, which might result in the formation of more tumor-related neo-antigens, had better responses to pembrolizumab. In malignancies including lymphomas and other solid tumors, preliminary data showed that ORRs of around 20-50 % could be achieved. Adverse events occurred in up to 60% of patients, but grade 3/4 toxicities were observed in <10% of cases. Immune-related adverse events including thyroid dysfunction, hepatitis and pneumonitis are more serious and may lead to cessation of treatment.

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“…9,11 Neurologic complications of checkpoint inhibitor therapies are also increasingly recognized, including headache, seizures, cranial neuropathies, and polyneuropathy. 12 A recent report 13 found that 2.9% of a 347-patient cohort treated with anti-PD1 therapy developed neurologic complications (predominantly myopathies and neuropathies). Cerebral vasculitis has been reported as a result of PD-1 inhibition in a recent case report.…”

Section: Discussionmentioning

confidence: 99%

Clinical Reasoning: A 77-year-old man presenting with episodic expressive aphasia

et al. 2018

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A 77-year-old white man presented to the emergency department with a 1-week history of episodic expressive aphasia, lasting between 3 and 30 minutes and increasing in frequency. He denied any associated symptoms with the aphasia and between episodes returned to baseline. His medical history included psoriatic arthritis, remote biopsy-confirmed giant cell arteritis (GCA), and metastatic urothelial adenocarcinoma for which he was being treated with programmed death ligand 1 (PD-L1) checkpoint inhibitor therapy.Initial neurologic examination, including language evaluation, was normal. The patient's musculoskeletal examination revealed features of chronic arthritis with dorsal hand soft tissue atrophy and bony joint hypertrophy without active synovitis. There were no findings of cutaneous, cardiopulmonary, or gastrointestinal abnormalities.The patient's initial brain MRI (figure) showed acute infarction in the right internal capsule. MRI fluid-attenuated inversion recovery sequence was otherwise unremarkable with minimal evidence of small vessel disease. CT angiogram was striking for several focal areas of high-grade stenosis of the large intracranial vessels: the right internal carotid artery (ICA) terminus, the proximal left M1 segment, and the left A1 origin had near-complete stenosis. In contrast, the other intracranial and extracranial neck vessels were patent with minimal atherosclerotic disease.The patient was started on dual antiplatelet therapy (aspirin and Plavix) as well as high-dose statin for severe, symptomatic large vessel intracranial stenosis.Questions for consideration: 1. What are the potential causes of focal proximal stenosis of the large intracranial arteries? 2. Given this differential diagnosis, what additional workup is recommended? GO TO SECTION 2

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Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy

Cited by 508 publications

References 32 publications

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

Pembrolizumab (Keytruda)

Clinical Reasoning: A 77-year-old man presenting with episodic expressive aphasia

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