Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

Adashek, Jacob J.; Kato, Shumei; Ferrara, Roberto; Russo, Giuseppe Lo; Kurzrock, Razelle

doi:10.1634/theoncologist.2019-0636

Cited by 64 publications

(43 citation statements)

References 56 publications

(141 reference statements)

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“…The amplified genes ( MDM2 / MDM4 / CCND1 / FGF3 / FGF4 / FGF19 ) have been suggested as genomic correlates of increased risk of hyperprogression after immune checkpoint inhibitors ( 19 ). Another study reported that CDK4 copy number gain was negatively correlated with anti-PD1 response in all subtypes of advanced melanoma and CCND1 copy number gain was associated with a lack of response to anti-PD-1 therapy in advanced acral melanoma ( 20 ).…”

Section: Resultsmentioning

confidence: 99%

Prior Therapy With Pegylated-Interferon Alfa-2b Improves the Efficacy of Adjuvant Pembrolizumab in Resectable Advanced Melanoma

et al. 2021

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Combination immunotherapy can overcome the limited objective response rates of PD-1 blockade. Interferon alpha (IFN-α) has been proven to be effective in modulating immune responses and may enhance the clinical responses to PD-1 blockade. According to clinical practice guidelines, IFN-α was recommended as adjuvant therapy for stage IIB/C melanoma patients. However, the impact of prior IFN-α therapy on the efficacy of subsequent PD-1 blockade in melanoma has not been previously reported. Therefore, we performed a retrospective analysis for melanoma patients and addressed whether prior IFN-α therapy enhanced adjuvant pembrolizumab as later-line treatment. Fifty-six patients with resectable stage III/IV melanoma who received adjuvant therapy with pembrolizumab were retrospectively enrolled in this study. Notably, 25 patients received adjuvant pegylated IFN-α (PEG-IFN-α) in the prior line of treatment while 31 patients did not receive prior PEG-IFN-α therapy. Cox regression analysis showed that prior PEG-IFN-α therapy was associated with the efficacy of later-line adjuvant pembrolizumab (hazard ratio=0.37, 95% CI 0.16-0.89; P = 0.026). The recurrence rates after treatment with adjuvant pembrolizumab were significantly reduced in the prior PEG-IFN-α group (P < 0.001). The Kaplan-Meier analysis also showed that recurrence-free survival (RFS) after adjuvant pembrolizumab therapy was prolonged by prior PEG-IFN-α treatment (median RFSPem 8.5 months vs. 4.5 months; P = 0.0372). These findings indicated that prior PEG-IFN-α could enhance the efficacy of adjuvant pembrolizumab. The long-lasting effects of PEG-IFN-α provide a new rationale for designing combination or sequential immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Prior Therapy With Pegylated-Interferon Alfa-2b Improves the Efficacy of Adjuvant Pembrolizumab in Resectable Advanced Melanoma

et al. 2021

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“…Unfortunately, the proportion of “responder” patients—that is to say, in whom the treatment is effective—varies considerably from one cancer to another. It can reach 40% in melanoma and is between 20% and 30% in the lung, but only 1% of patients with pancreatic cancer are responders [ 116 , 117 ]. This disparity could be explained by the fact that the immune system must recognize the tumor as a foreign body that needs to be eliminated.…”

Section: Discussionmentioning

confidence: 99%

PD-1/PD-L1 Checkpoints and Resveratrol: A Controversial New Way for a Therapeutic Strategy

Delmas

Hermetet

Aires

2021

Cancers

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Immune checkpoints refer to a range of immunoregulatory molecules that modulate the immune response. For example, proteins expressed at the surface of T-cells (including PD-1 and CTLA-4) and their ligands (PD-L1 and B7-1/B7-2, respectively), expressed by cancer cells and antigen-presenting cells, are needed to prevent excessive immune responses. However, they dampen anti-tumor immunity by limiting T-cell activity, making them promising therapeutic targets in cancer. Although immunotherapies using checkpoint blocking/neutralizing antibodies targeting PD-L1 or PD-1 have proven their superiority over conventional chemotherapies or targeted therapies by enhancing T-cell-mediated anti-tumor immunity, some limitations have emerged. These include a relatively low rate of “responders” (<50%; irrespective of cancer type), the high cost of injections, and a rare risk of hyper-progression. For clinicians, the current challenge is thus to improve the existing therapies, potentially through combinatory approaches. Polyphenols such as resveratrol (RSV), a trihydroxystilbene found in various plants and an adjuvant in numerous nutraceuticals, have been proposed as potential therapeutic targets. Beyond its well-known pleiotropic effects, RSV affects PD-L1 and PD-1 expression as well as PD-L1 subcellular localization and post-translational modifications, which we review here. We also summarize the consequences of PD-1/PD-L1 signaling, the modalities of their blockade in the context of cancer, and the current status and limitations of these immunotherapies. Finally, we discuss their potential use in combination with chemotherapies, and, using RSV as a model, we propose polyphenols as adjuvants to enhance the efficacy of anti-PD-1/anti-PD-L1 immunotherapies.

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“…No validated clinical or molecular predictors of HPD have been identified due to the heterogeneity and retrospective nature of the studies. Furthermore, there is no consensus on HPD definition and distinct criteria (i.e., one-dimensional, volumetric or clinical) have been proposed (15)(16)(17).…”

Section: Methodsmentioning

confidence: 99%

Novel patterns of progression upon immunotherapy in other thoracic malignancies and uncommon populations

Ferrara¹,

Signorelli²,

Proto³

et al. 2021

Transl Lung Cancer Res

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In the immunotherapy era, considering the prolonged survival benefit and responses observed with immunecheckpoint inhibitors (ICI) in many cancer types, the identification of patients with rapid progression (PD) and deaths upon ICI has found some skepticism and resistance among the scientific community. Nevertheless, an acceleration of tumour during ICI, defined as hyperprogressive disease (HPD), has been recognized across different cancer types and evidence regarding rapid PDs and deaths are emerging in patients with malignant pleural mesothelioma (MPM), small cell lung cancer (SCLC) and thymic malignancies and in uncommon non-small cell lung cancer (NSCLC) populations. Of note, PD and early deaths (ED) rates upon single agent ICI were up to 60% and 30% in MPM and 70% and 38% in SCLC patients, respectively. Similarly, rapid PDs and deaths were observed in clinical trials and retrospective studies including patients with poor performance status (PS), HIV infection and rare NSCLC histologies. Atypical patterns of response, such as pseudoprogression (PsPD) may also occur in other thoracic malignancies (MPM) and in some uncommon populations (i.e., HIV patients), however probably at lower rate compared to HPD.The characterizations of HPD and PsPD mechanisms and the identification of common definition criteria are the next future challenges in this area of cancer research.

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Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

Cited by 64 publications

References 56 publications

Prior Therapy With Pegylated-Interferon Alfa-2b Improves the Efficacy of Adjuvant Pembrolizumab in Resectable Advanced Melanoma

Prior Therapy With Pegylated-Interferon Alfa-2b Improves the Efficacy of Adjuvant Pembrolizumab in Resectable Advanced Melanoma

PD-1/PD-L1 Checkpoints and Resveratrol: A Controversial New Way for a Therapeutic Strategy

Novel patterns of progression upon immunotherapy in other thoracic malignancies and uncommon populations

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