Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions

Hassel, Jessica C.; Heinzerling, Lucie; Aberle, Jens; Bähr, Oliver; Eigentler, Thomas; Grimm, Marc‐Oliver; Grunwald, Victor; Leipe, Jan; Reinmuth, Niels; Tietze, Julia K.; Trojan, Jörg; Zimmer, Lisa; Gutzmer, Ralf

doi:10.1016/j.ctrv.2017.05.003

Cited by 267 publications

(261 citation statements)

References 116 publications

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“…4,5 Moreover, some treatment-related toxicities have been observed which limit the use of these drugs, especially when both anti-PD1 and anti-CTLA-4 were combined. 6 To overcome the current limitations of immune checkpoint immunotherapy, methods to enhance the efficacy and safety would be advantageous. 7 In this regard, a large number of trials are now underway that combine checkpoint blockade with a wide range of therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody. The involvement of p53 in enhancing anti-PD1 immunotherapy appears to be multifaceted, since SGT-53 treatment increased tumor immunogenicity, enhanced both innate and adaptive immune responses, and reduced tumor-induced immunosuppression in a 4T1 breast tumor model. In addition, SGT-53 alleviates a fatal xenogeneic hypersensitivity associated with the anti-PD1 antibody in this model. Our data suggest that restoring p53 function by SGT-53 is able to boost anti-tumor immunity to augment anti-PD1 therapy by sensitizing tumors otherwise insensitive to anti-PD1 immunotherapy while reducing immune-related adverse events.

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Section: Introductionmentioning

confidence: 99%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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“…Anti‐CTLA‐4 and anti‐PD‐1 antibodies, amongst others Ipilimumab, Nivolumab or Pembrolizumab, have demonstrated durable remissions as well as prolongation of survival in oncologic patients. Interestingly, although complete remission rates in patients treated with CKi range below 15%, long‐term survival and persistent long‐term disease stabilization has been observed even years after finishing CKi treatment, CKi treatment is now approved for several malignancies, including amongst others melanoma, non‐small lung cancer and Hodgkin's lymphoma . Remarkable clinical activity of CKis urges their combination with CAR T cells.…”

Section: Enhancing Car Efficacy Via Combination Therapymentioning

confidence: 99%

Chimeric antigen receptor transduced T cells: Tuning up for the next generation

Schubert

Hoffmann

Dreger

et al. 2017

Intl Journal of Cancer

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Chimeric antigen receptor (CAR) T cell therapy has recently achieved impressive clinical outcome in patients with CD19-positive hematologic malignancies. Extrapolation of CAR T cell treatment to solid tumors, however, has not yet yielded similar results. This might be due to intrinsic causes, e.g. insufficient CAR T cell activation or CAR toxicity as well as extrinsic factors displaying an unfavorable tumor environment for CAR T cells by raising physical and chemical barriers. In this review, we discuss the advantages as well as major obstacles of CAR T cell therapy, particularly in the context of solid tumors, and focus on efforts and novel strategies in CAR T cell development.

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“…While ICIs have substantially improved cancer outcomes, inhibiting immune regulatory mechanisms can also result in unique toxicities, termed immune related adverse events (irAEs), which include, but are not limited to, colitis, hepatitis, dermatitis, pneumonitis and endocrinopathies such as hypophysitis [3, 4]. The inflammatory conditions brought on by immunotherapy are varied and unpredictable [5, 6].…”

Section: Introductionmentioning

confidence: 99%

Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report

Appelbaum¹,

Wells²,

Hiatt³

et al. 2018

j. immunotherapy cancer

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BackgroundImmune checkpoint inhibitors (ICIs) are the treatment of choice for several cancers and can be associated with remarkable clinical benefit, but can also cause serious immune-related adverse events (irAEs). Management of rare and severe irAEs is challenged by an incomplete knowledge of their natural history and pathogenetic mechanisms. We report a case of fatal acute-onset gastro-intestinal (GI) hypomotility from myenteric plexus neuropathy following a single dose of ipilimumab plus nivolumab given for treatment of Merkel cell carcinoma (MCC).Case presentationA 66-year-old man with recurrent metastatic MCC involving several organs (liver, bones and disseminated retroperitoneal lymphadenopathy) developed profound pharyngeal dysphagia and ileus that started 7 days after receiving a single administration of combination immune checkpoint blockade consisting of nivolumab (3 mg/kg) and low-dose ipilimumab (1 mg/kg). A swallowing study showed oropharyngeal dysfunction and aspiration. Imaging studies were consistent with diffuse intestinal paresis. An extensive work-up did not reveal obvious causes of these symptoms, and enteric plexopathy was suspected. Empiric immune suppressive therapy was initiated urgently. Despite an escalating immunosuppressive regimen that included high dose steroids, tacrolimus and therapeutic plasma exchange, no improvement in GI motility was seen and the patient suffered repeated episodes of aspiration. Seven weeks after the onset of GI hypomotility, the patient succumbed to sepsis from intestinal perforations. At autopsy, histologic specimens obtained from the entire GI tract (pharynx to rectum) showed near complete loss of ganglion cells within the myenteric and submucosal plexuses. An associated inflammatory infiltrate was not seen, suggesting a ‘burned out’ phase of illness. C4d complement deposition was found at the ganglionic sites, suggesting antibody-mediated pathogenesis. Remarkably, at sites of previously suspected Merkel cell metastases, no residual viable Merkel cell carcinoma was identified.ConclusionsGI-tract paresis due to myenteric neuritis is a rarely reported toxicity of ICIs. Because the window of reversibility is likely to be very brief, quick and decisive interventions are warranted. Subtle functional and anatomic perturbations of the myenteric nervous system from the use of ICIs may be more prevalent than realized and should be suspected and addressed in both clinical and investigational settings.

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Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions

Cited by 267 publications

References 116 publications

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Chimeric antigen receptor transduced T cells: Tuning up for the next generation

Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report

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