Durable Response and Good Tolerance to the Triple Combination of Toripalimab, Gemcitabine, and Nab-Paclitaxel in a Patient With Metastatic Pancreatic Ductal Adenocarcinoma

Shui, Lin; Cheng, Ke; Li, Xiaofen; Shui, Pixian; Li, Shuangshuang; Peng, Yang; Li, Jian; Guo, Fengzhu; Yi, Cheng; Cao, Dan

doi:10.3389/fimmu.2020.01127

Cited by 11 publications

(10 citation statements)

References 30 publications

(22 reference statements)

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“…In a randomized phase II study involving 34 pre‐operative pancreatic cancer patients, high‐dose hydroxychloroquine combined with gemcitabine/nab‐paclitaxel was shown to increase the TME immune infiltration score, which is associated with significantly improved ( p < 0.0001) progression‐free and overall survival, compared to the results of 30 patients who received only gemcitabine/nab‐paclitaxel. Signs of enhanced anti‐PDAC efficacy for gemcitabine/nab‐paclitaxel using the PD‐1 antibodies toripalimab and pembrolizumab were evident in patients with a durable response 44 and a 100% disease control rate (27% PR + 73% SD) for 11 evaluable patients. 45 …”

Section: Discussionmentioning

confidence: 99%

“…In a randomized phase II study involving 34 pre-operative pancreatic cancer patients, high-dose hydroxychloroquine combined with gemcitabine/ nab-paclitaxel was shown to increase the TME immune infiltration score, which is associated with significantly improved (p < 0.0001) progression-free and overall survival, compared to the results of 30 patients who received only gemcitabine/nab-paclitaxel. Signs of enhanced anti-PDAC efficacy for gemcitabine/nab-paclitaxel using the PD-1 antibodies toripalimab and pembrolizumab were evident in patients with a durable response44 and a 100% disease control rate (27% PR + 73% SD) for 11 evaluable patients 45. In light of the potential efficacy of Abraxane combined with immunotherapy, tens of clinical trials of this combinational regimen for patients with PDAC have been undertaken, as shown in the search results of the www.clini caltr ials.gov database using a search with keywords including pancreatic cancer, nab-paclitaxel and immunotherapy.…”

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confidence: 99%

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Synergistic effect of Abraxane that combines human IL15 fused with an albumin‐binding domain on murine models of pancreatic ductal adenocarcinoma

Hsu

Tsai

Chiang

et al. 2022

J Cellular Molecular Medi

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Nab-paclitaxel (Abraxane), which is a nanoparticle form of albumin-bound paclitaxel, is one of the standard chemotherapies for pancreatic ductal adenocarcinoma (PDAC).This study determined the effect of Abraxane in combination with a fusion protein, hIL15-ABD, on subcutaneous Panc02 and orthotopic KPC C57BL/6 murine PDAC models. Abraxane combined with hIL15-ABD best suppressed tumour growth and produced a 40%-60% reduction in the tumour size for Panc02 and KPC, compared to the vehicle group. In the combination group, the active form of interferonγ (IFNγ)-secreting CD8 + T cells and CD11b + CD86 + M1 macrophages in tumour infiltrating lymphocytes (TILs) were increased. In the tumour drainage lymph nodes (TDLNs) of the combination group, there was a 18% reduction in CD8 + IFNγ + T cells and a 0.47% reduction in CD4 + CD25 + FOXP3 + regulatory T cells, as opposed to 5.0% and 5.1% reductions, respectively, for the control group. Superior suppression of CD11b + GR-1 + myeloid-derived suppressor cells (MDSCs) and the induction of M1 macrophages in the spleen and bone marrow of mice were found in the combination group. Abraxane and hIL15-ABD effectively suppressed NF-κB-mediated immune suppressive

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Synergistic effect of Abraxane that combines human IL15 fused with an albumin‐binding domain on murine models of pancreatic ductal adenocarcinoma

Hsu

Tsai

Chiang

et al. 2022

J Cellular Molecular Medi

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“…Additionally, PD-L1 positive expression was detected in liver metastases in a patient with metastatic PC who had received toripalimab (240 mg Q3W) and gemcitabine (1000 mg/m 2 on day 1 and 8 every 3 weeks) plus nab-paclitaxel (125 mg/m 2 on day 1 and 8 every 3 weeks). As a result, he experienced long-term PR (8 cycles at the time of the report) but did not suffer any grade 3 or higher toxicity [ 38 ]. A phase Ib/II study in which toripalimab, gemcitabine, and nab-paclitaxel were combined to treat patients with nonresectable PC was initiated by the same center (ChiCTR2000032293, [ 39 ].…”

Section: Combination With Chemotherapymentioning

confidence: 99%

Combination therapy for pancreatic cancer: anti-PD-(L)1-based strategy

Liu

Huang

Shi

et al. 2022

J Exp Clin Cancer Res

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Mortality associated with pancreatic cancer is among the highest of all malignancies, with a 5-year overall survival of 5–10%. Immunotherapy, represented by the blocking antibodies against programmed cell death protein 1 or its ligand 1 (anti-PD-(L)1), has achieved remarkable success in a number of malignancies. However, due to the immune-suppressive tumor microenvironment, the therapeutic efficacy of anti-PD-(L)1 in pancreatic cancer is far from expectation. To address such a fundamental issue, chemotherapy, radiotherapy, targeted therapy and even immunotherapy itself, have individually been attempted to combine with anti-PD-(L)1 in preclinical and clinical investigation. This review, with a particular focus on pancreatic cancer therapy, collects current anti-PD-(L)1-based combination strategy, highlights potential adverse effects of accumulative combination, and further points out future direction in optimization of combination, including targeting post-translational modification of PD-(L)1 and improving precision of treatment.

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“…33 A case has reported that a patient with MPC has a long-term partial response and good tolerance to toripalimab plus gemcitabine and nab-paclitaxel. 34 Besides, a phase study found signi cant improved PFS and OS among patients with metastatic non-squamous NSCLC attributed to the addition of atezolizumab to bevacizumab, carboplatin and paclitaxel, which provide compelling evidence that the cancer-cell-killing effects of PD-1 blockade could be enhanced by immunoregulation mediated by cytotoxic chemotherapy and anti-angiogenesis. 35 Thus, combining toripalimab with cytotoxic nab-paclitaxel and small-molecule multi-receptor TKI may become a potential therapeutic strategy for LAPC or MPC patients.…”

Section: Introductionmentioning

confidence: 99%

Anlotinib Plus Toripalimab and Nab-Paclitaxel in Patients with Locally Advanced or Metastatic Pancreatic Cancer: Study Protocol for An Open-Label, Non-Randomized, Phase II Study (ATNPA)

Chen

Zhu

Cui

et al. 2021

Preprint

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Background There have not been standard second-line or maintenance regimens with definite survival benefits so far for patients with pancreatic carcinoma who have lost the opportunity of curable resections or failed first-line chemotherapy. Anlotinib, a potent small-molecule tyrosine kinase inhibitor, exhibits anti-angiogenic and anti-tumour effects by specifically binding to multiple targets such as VEGFR, FGFR, PDGFR, c-Kit and Ret. Toripalimab, a novel anti-PD-1 mAb, has been proved to significantly prolong progression-free survival (PFS) and overall survival (OS) in various solid tumours with manageable toxicities when combining with cytotoxic chemotherapy. We design this study to assess the combination of anlotinib, toripalimab and nab-paclitaxel as a second-line or maintenance therapy for locally advanced pancreatic cancer (LAPC) or metastatic pancreatic cancer (MPC). Patients and Methods: This is an open-label, non-randomized, single-arm phase Ⅱ study, aimed at evaluating the efficacy and safety profile of the above-mentioned combination strategy in first-line therapy-failed LAPC or MPC. Totally 53 patients are to be enrolled and receive anlotinib (12 mg, po. qd.) plus toripalimab (240 mg, ivgtt. q3w.) and nab-paclitaxel (125 mg/m2, ivgtt, d1, d8) every 3 weeks as a cycle until disease progression or intolerable adverse events. The primary endpoint is PFS. Secondary end points include OS, disease control rate (DCR), object response rate (ORR), quality of life (QoL) and safety. Enrollment started in April 2021, and follow-up will be finished in April 2023. Discussion and Significance: Combination of anlotinib, toripalimab and nab-paclitaxel may promote vessel normalization and drug delivery, and activate the immune response, thus exerting synergistic anti-tumour effects and counteracting the immunosuppressive microenvironment of pancreatic cancer. As the first intending to assess this combination in pancreatic cancer, this study will provide comprehensive evidence for second-line or maintenance therapy of LAPC and MPC. Trial registration: ClinicalTrials.gov: ATNPA, NCT04718701. Registered January 22, 2021. (https://clinicaltrials.gov/ct2/show/NCT04718701?term=NCT04718701&draw=2&rank=1)

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Durable Response and Good Tolerance to the Triple Combination of Toripalimab, Gemcitabine, and Nab-Paclitaxel in a Patient With Metastatic Pancreatic Ductal Adenocarcinoma

Cited by 11 publications

References 30 publications

Synergistic effect of Abraxane that combines human IL15 fused with an albumin‐binding domain on murine models of pancreatic ductal adenocarcinoma

Synergistic effect of Abraxane that combines human IL15 fused with an albumin‐binding domain on murine models of pancreatic ductal adenocarcinoma

Combination therapy for pancreatic cancer: anti-PD-(L)1-based strategy

Anlotinib Plus Toripalimab and Nab-Paclitaxel in Patients with Locally Advanced or Metastatic Pancreatic Cancer: Study Protocol for An Open-Label, Non-Randomized, Phase II Study (ATNPA)

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