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Clinical Trial
. 2020 Jul 15;26(14):3578-3588.
doi: 10.1158/1078-0432.CCR-19-3978. Epub 2020 Apr 9.

Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer (V体育官网)

Takahiro Tsujikawa  1 , Todd Crocenzi  2 , Jennifer N Durham  3 , Elizabeth A Sugar  3 , Annie A Wu  3 , Beth Onners  3 , Julie M Nauroth  3 , Robert A Anders  3 , Elana J Fertig  3 , Daniel A Laheru  3 , Kim Reiss  4 , Robert H Vonderheide  4 , Andrew H Ko  5 , Margaret A Tempero  5 , George A Fisher  6 , Michael Considine  3 , Ludmila Danilova  3 , Dirk G Brockstedt  7 , Lisa M Coussens  1 , Elizabeth M Jaffee  3 , Dung T Le  8
Affiliations
Clinical Trial

VSports app下载 - Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer

Takahiro Tsujikawa et al. Clin Cancer Res. .

Abstract

Purpose: Two studies in previously treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (GM-CSF-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes-expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B). VSports手机版.

Patients and methods: Patients with pancreatic adenocarcinoma who received one prior therapy for metastatic disease and RECIST measurable disease were randomized 1:1 to receive treatment on Arm A or Arm B V体育安卓版. The primary objective was to compare overall survival (OS) between the arms. Additional objectives included assessment of progression-free survival, safety, tumor responses, CA19-9 responses, and immunologic correlates. .

Results: Ninety-three patients were treated (Arm A, 51; Arm B, 42). The median OS in Arms A and B were 5. 9 [95% confidence interval (CI), 4. 7-8. 6] and 6. 1 (95% CI, 3. 5-7. 0) months, respectively, with an HR of 0 V体育ios版. 86 (95% CI, 0. 55-1. 34). Objective responses were seen in 3 patients using immune-related response criteria (4%, 2/51, Arm A; 2%, 1/42, Arm B). The grade ≥3 related adverse event rate, whereas higher in Arm A (35. 3% vs. 11. 9%) was manageable. Changes in the microenvironment, including increase in CD8+ T cells and a decrease in CD68+ myeloid cells, were observed in long-term survivors in Arm A only. .

Conclusions: Although the study did not meet its primary endpoint of improvement in OS of Arm A over Arm B, the OS was comparable with standard therapy VSports最新版本. Objective responses and immunologic changes in the tumor microenvironment were evident. .

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Conflict of interest statement

Conflict of Interest Statement: T. Tsujukawa is a consultant for Konica Minolta and Ono Pharmaceutical. T. Crocenzi has received research support from Bristol-Myers Squibb and AstraZeneca. R. A. Anders is on the scientific advisory board or receives research support from Merck, Bristol-Myers Squibb, FLX Bio, Incyte and Adaptive Biotech. E. J. Fertig is a consultant for Champions Oncology. K. A. Reiss has research support from Clovis, Bristol-Myer Squibb, Tesaro and Lilly Oncology. R. H. Vonderheide reports having received consulting fees or honoraria from Apexigen, AstraZeneca, Celgene, Genentech, Janssen, Lilly, Medimmune, Merck and Verastem. He has received research funding from Apexigen, Fibrogen, Inovio, Janssen, and Lilly. He is an inventor on a licensed patent relating to cancer cellular immunotherapy and receives royalties from Children’s Hospital Boston for a licensed research-only monoclonal antibody VSports注册入口. A. H. Ko has received research support from Aduro Biotech and Bristol-Myers Squibb. G. A. Fisher serves on advisory boards for or received honoraria from Merck, Roche/Genentech, Aduro Biotech, and FortySeven. He serves on Data Safety Monitoring Committees for Celgene, CytomX, Silenseed, Terumo, and AstraZeneca. D. G. Brockstedt is a former employee of and is a shareholder in Aduro Biotech. L. M. Coussens is a paid consultant for Cell Signaling Technologies, received reagent and/or research support from Plexxikon Inc. , Pharmacyclics, Inc. , Acerta Pharma, LLC, Deciphera Pharmaceuticals, LLC, Genentech, Inc. , Roche Glycart AG, Syndax Pharmaceuticals Inc. , and NanoString Technologies, and is a member of the Scientific Advisory Boards of Syndax Pharmaceuticals, Carisma Therapeutics, Zymeworks, Inc, Verseau Therapeutics, and Cytomix Therapeutics, Inc. E. M. Jaffee and Johns Hopkins University have the potential receive royalties from Aduro Biotech which owns the license to GVAX and Listeria Monocytogenes-mesothelin. E. Jaffee is the Chief Medical Advisor for the Lustgarten Foundation and is active on the scientific advisory boards of Genocea, Adaptive Biotech, DragonFly, CSTONE, Achilles, Parker Institute and the National Cancer Advisory Board. She receives research funding from Aduro Biotech, Amgen, Bristol-Myers Squibb, Hertix and Corvus. D. Le serves on the advisory boards for Merck and Bristol-Myers Squibb and has received research funding from Merck, Bristol-Myers Squibb, Aduro Biotech, Curegenix, Medivir and Nouscom. She has received speaking honoraria from Merck.

"VSports手机版" Figures

Figure 1.
Figure 1.. Treatment schema.
Patients with previously treated, metastatic pancreatic cancer were randomized 1:1 to 2 treatment arms (Arm A: Cy/GVAX & CRS-207 + Nivolumab vs. Arm B: Cy/GVAX & CRS-207). Cycles were administered at 3 week intervals. Cyclophosphamide and nivolumab were administered on days 1, GVAX and CRS-207 were administered on days 2. A course was 6 cycles and courses could be repeated.
Figure 2.
Figure 2.. Overall survival.
A comparison of overall survival in months for treatment groups A versus B.
Figure 3.
Figure 3.. Treatment Effect by Baseline Characteristics.
Forest plot of the treatment effect within subgroups defined by baseline demographic, disease, and treatment characteristics. NA and NB represent the number within in each subgroup in Arms A and B, respectively. Both the hazard ratio within each subgroup and the hazard ratio of the interaction comparing the subgroups are provided. RZ = randomization.
Figure 4.
Figure 4.. Maximum decrease in the sum of longest diameters in the target lesions
Figure 5.
Figure 5.. Delayed response after RECIST v.1.1 progression and associated immune infiltration.
A-C) Baseline, week 10, and week 30 scans of a patient treated on Arm A demonstrating growth followed by regression (immune related response at week 30). D) Top panel: Archived pancreas tumor shows expression of PD-L1 membranous staining and few CD8 and CD3 T cells. Bottom panel: On treatment lung metastases shows expected pattern of PD-L1 expression on CD68 macrophages as well CD8 and CD3 T cell infiltration.
Figure 6.
Figure 6.. Longitudinal changes of immune cell complexity profiles in association with overall survival (OS).
FFPE tissue sections derived from biopsies obtained at baseline and at the post cycle (Cy 3) were subjected to immune-detection by the three 12-marker panels of lymphoid and myeloid lineages, and T cells (Supplementary Table 1). (A) Immune cell densities (cell number per mm2) of CD8+ T cell, other lymphoid lineages cells, CD68+CSF1R+ tumor associated macrophages (TAMs), CD66b+ granulocytes, and other myeloid cell lineages are shown, comparing baseline and post Cy3 status among short and long OS groups. (B) The ratios of lymphoid to myeloid cell densities are shown, comparing baseline and post Cy3 status among short and long OS groups. (C, E) Multiplex IHC images for T cell lineages (C) and myeloid cell lineages (E), comparing baseline and post Cy3 of ADU-CL-06–001-022 in arm A. Color annotations and scales were shown. (D, F) Frequency of CD8+ T cells (D) and CD68+ myeloid cells (F) are exhibited as cell percentages of total CD45+ immune cells, comparing baseline and post Cy3 status among short and long OS groups. * and ** indicate P < 0.05 and 0.01, respectively.
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References

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