Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination With Pegilodecakin in Patients With Metastatic NSCLC (CYPRESS 1 and CYPRESS 2)

Spigel, David R.; Jotte, Robert M.; Nemunaitis, John; Shum, M.; Schneider, Jeffrey; Goldschmidt, Jerome H.; Eisenstein, Jennifer; Berz, David; Seneviratne, Lasika; Socoteanu, Matei P.; Bhanderi, Viralkumar K.; Konduri, Kartik; Xia, Meng; Wang, Hong; Hozak, Rebecca R.; Gueorguieva, Ivelina; Ferry, David; Gandhi, Leena; Chao, Bo H.; Rybkin, Igor I.

doi:10.1016/j.jtho.2020.10.001

Cited by 31 publications

(17 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, IL-10 agonism and antagonism have been observed to enhance anti-tumor outcomes, preclinically [114,115]. Despite promising early phase results, IL-10 agonist, pegilodecakin, failed to enhance response to FOLFOX in the 2nd line for mPDAC [116] and led to increased toxicity without enhancing survival when paired with aPD-1 therapy in NSCLC [117]. Human trials with IL-10 inhibition are limited.…”

Section: Il-10 Modulationmentioning

confidence: 99%

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

Heumann

Azad

2021

Cancer Metastasis Rev

View full text Add to dashboard Cite

To date, the use of immune checkpoint inhibitors has proven largely ineffective in patients with advanced pancreatic ductal adenocarcinoma. A combination of low tumor antigenicity, deficits in immune activation along with an exclusive and suppressive tumor microenvironment result in resistance to host defensives. However, a deepening understanding of these immune escape and suppressive mechanisms has led to the discovery of novel molecular targets and treatment strategies that may hold the key to a long-awaited therapeutic breakthrough. In this review, we describe the tumor-intrinsic and microenvironmental barriers to modern immunotherapy, examine novel immune-based and targeted modalities, summarize relevant pre-clinical findings and human experience, and, finally, discuss novel synergistic approaches to overcome immune-resistance in pancreatic cancer. Beyond checkpoint inhibition, immune agonists and anti-tumor vaccines represent promising strategies to stimulate host response via activation and expansion of anti-tumor immune effectors. Off-the-shelf natural killer cell therapies may offer an effective method for bypassing downregulated tumor antigen presentation. In parallel with this, sophisticated targeting of crosstalk between tumor and tumor-associated immune cells may lead to enhanced immune infiltration and survival of antitumor lymphocytes. A future multimodal treatment strategy involving immune priming/activation, tumor microenvironment reprogramming, and immune checkpoint blockade may help transform pancreatic cancer into an immunogenic tumor.

show abstract

Section: Il-10 Modulationmentioning

confidence: 99%

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

Heumann

Azad

2021

Cancer Metastasis Rev

View full text Add to dashboard Cite

show abstract

“…In relapsed pancreatic cancer, a phase III clinical trial showed no statistical difference between FOLFOX (folinic acid + fluorouracil + oxaliplatin) in association with pegylated IL-10 compared to FOLFOX alone [62]. Unfortunately, in metastatic NSCLC patients, the addition of IL-10 to PD-L1 inhibitors, either nivolumab or pembrolizumab, did not bring any benefit [63].…”

Section: Il-10 As An Anti-tumor Cytokinementioning

confidence: 99%

The Potential Advantage of Targeting Both PD-L1/PD-L2/PD-1 and IL-10–IL-10R Pathways in Acute Myeloid Leukemia

et al. 2021

View full text Add to dashboard Cite

Tumor cells promote the suppression of host anti-tumor type 1 T cell responses by various mechanisms, including the upregulation of surface inhibitory molecules such as programmed death ligand (PD-L)-1, and the production of immunosuppressive cytokines such as interleukin-10 (IL-10). There are over 2000 trials investigating PD-L1 and/or its receptor programmed-death 1 (PD-1) blockade in cancer, leading to the approval of PD-1 or PD-L1 inhibitors in several types of solid cancers and in hematological malignancies. The available data suggest that the molecule PD-L1 on antigen-presenting cells suppresses type 1 T cell immune responses such as cytotoxicity, and that the cytokine IL-10, in addition to downregulating immune responses, increases the expression of inhibitory molecule PD-L1. We hypothesize that the manipulation of both the co-inhibitory network (with anti-PD-L1 blocking antibodies) and suppressor network (with anti-IL-10 blocking antibodies) is an attractive immunotherapeutic intervention for acute myeloid leukemia (AML) patients ineligible for standard treatment with chemotherapy and hematopoietic stem cell transplantation, and with less severe adverse reactions. The proposed combination of these two immunotherapies represents a new approach that can be readily translated into the clinic to improve the therapeutic efficacy of AML disease treatment.

show abstract

“…13,14,16 Pegilodecakin exhibited single-agent activity in renal cell carcinoma and melanoma, and correlative studies support evidence of pharmacodynamic activity at the recommended phase 2 dose and schedule. 11,16,17 Evidence of immune activation and reduction of immunosuppressive TGF-b levels were seen with pegilodecakin in CYPRESS-1 and -2, but these did not translate into better clinical outcomes. Did the changes in peripheral blood reflect changes in the tumor?…”

mentioning

confidence: 99%

“…In this issue of the Journal, Spigel et al 11 present the results of two randomized signal-finding trials in checkpoint inhibitor-naive patients, adding pegilodecakin to PD-1 inhibitor monotherapy. Pegilodecakin is a recombinant pegylated formulation of interleukin (IL)-10 that allows longer half-life and greater antitumor activity in preclinical and clinical studies.…”

mentioning

confidence: 99%

“…These exciting but early observations led to the CYPRESS-1 and -2 trials. 11 In CYPRESS-1, a total of 101 treatment-naive patients with advanced NSCLC without targetable EGFR or ALK aberrations and PD-L1 TPS of 50% or greater were randomized to receive pembrolizumab with or without pegilodecakin. In CYPRESS-2, a total of 52 checkpoint inhibitor-naive patients with PD-L1 TPS less than 50% that had received previous chemotherapy were randomized to receive nivolumab with or without pegilodecakin.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Meeting Immunotherapy Resistance in Lung Cancer

Leighl

2021

Journal of Thoracic Oncology

View full text Add to dashboard Cite

Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination With Pegilodecakin in Patients With Metastatic NSCLC (CYPRESS 1 and CYPRESS 2)

Cited by 31 publications

References 10 publications

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

The Potential Advantage of Targeting Both PD-L1/PD-L2/PD-1 and IL-10–IL-10R Pathways in Acute Myeloid Leukemia

Meeting Immunotherapy Resistance in Lung Cancer

Contact Info

Product

Resources

About