scholarly journals Recent Advances in the Clinical Development of Immune Checkpoint Blockade Therapy for Mismatch Repair Proficient (pMMR)/non-MSI-H Metastatic Colorectal Cancer

2018 ◽  
Vol 17 (4) ◽  
pp. 258-273 ◽  
Author(s):  
James J. Lee ◽  
Edward Chu
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Clinical Development ◽  
Checkpoint Blockade ◽  
Recent Advances

23 Circulating tumor DNA (ctDNA) serial analysis during progression on PD-1 blockade and later CTLA4 rescue in patients with mismatch repair deficient metastatic colorectal cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A22-A22
Author(s):  
Pashtoon Kasi ◽  
Carlos Chan
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Circulating Tumor Dna ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency ◽  
Tumor Dna

BackgroundPatients with mismatch repair deficient/microsatellite instability high (dMMR/MSI-High) tumors respond well to immune checkpoint blockade.1 2 Pembrolizumab was the first drug to be approved by the FDA in an agnostic fashion for any tumor type with dMMR/MSI-High for the very same reason. The responses in dMMR/MSI-High tumors tend to be brisk, dramatic and durable to the point that the word ‘cure’ is being used for patients who do respond to PD-1 blockade. This year, pembrolizumab now got approval as 1st line therapy for dMMR/MSI-High metastatic colorectal cancers as well. However, a third of patients do not respond.3 Predictive markers and data for subsequent therapy options are lacking. Here we present for the first time a series of dMMR/MSI-High patients who not only had serial circulating tumor DNA (ctDNA) monitoring during PD-1 blockade/progression, but also were able to get anti-CTLA4 in conjunction with an anti-PD1 (‘CTLA4-rescue’), with ctDNA trends predicting responses weeks ahead of standard imaging.MethodsMetastatic colorectal cancer patients enrolled in the expanded access program for tumor informed circulating tumor DNA monitoring (Signatera 16-plex bespoke mPCR NGS assay) who were noted to be dMMR/MSI-High colorectal cancers were identified. Serial monitoring results while they were receiving immune checkpoint blockade therapy is presented. This only includes patients who had progression on PD-1 blockade whereby CTLA-4 rescue was done as part of their treatment strategy.ResultsSerial monitoring and trends of progression followed by responses are depicted in the patients who had CTLA-4 rescue post PD-1 progression (figure 1). This correlated with radiographic responses in all the patients. The ctDNA decreases in patients showing responses as well as ctDNA increases earlier during progression on PD-1 blockade happened within administration of a single dose.Abstract 23 Figure 1Example of a patient with serial tumor-informed ctDNA monitoring showing initial response and subsequent progression on PD-1 blockade followed by ‘CTLA-4 rescue’.ConclusionsTo date there is only 1 case report published earlier this year showing the value of ‘immunotherapy after immunotherapy’ in patients with dMMR/MSI-High tumors. Here we not only present a series of patients but also in parallel provide a snapshot on serial ctDNA trends whereby this could serve as a dynamic predictive marker of early response or progression to therapy.4 5 Finally, ‘CTLA4-rescue’ needs to be formally included in NCCN and other respective guidelines. Even though nivolumab/ipilimumab is listed as an option for dMMR/MSI-High tumors in addition to single agent pembrolizumab or nivolumab, it is not listed as an option post-PD-1 progression. For all the patients, we have had to fight to get peer to peer approval.Ethics ApprovalThe study is approved at University of Iowa and part of IRB#201202743.ConsentWritten informed consent was obtained from the patients for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferencesLe DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409–13. [Crossref] [PubMed]Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509–20. [Crossref] [PubMed]Andre T, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. J Clin Oncol 2020;38:LBA4.Anagnostou V, Forde PM, White JR, et al. Dynamics of tumor and immune responses during immune checkpoint blockade in non-small cell lung cancer. Cancer Res 2019;79:1214–25. [Crossref] [PubMed]Phallen J, Leal A, Woodward BD, et al. Early noninvasive detection of response to targeted therapy in non-small cell lung cancer. Cancer Res 2019;79:1204–13.

scholarly journals Dendritic cell paucity in mismatch repair–proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy

2021 ◽  
Vol 118 (45) ◽  
pp. e2105323118
Author(s):  
William W. Ho ◽  
Igor L. Gomes-Santos ◽  
Shuichi Aoki ◽  
Meenal Datta ◽  
Kosuke Kawaguchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair–proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.

scholarly journals Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer

2019 ◽  
Vol 7 (8) ◽  
pp. 1230-1236 ◽  
Author(s):  
Carino Gurjao ◽  
David Liu ◽  
Matan Hofree ◽  
Saud H. AlDubayan ◽  
Isaac Wakiro ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Intrinsic Resistance

Recent advances in the clinical development of immune checkpoint blockade therapy

2019 ◽  
Vol 42 (5) ◽  
pp. 609-626 ◽  
Author(s):  
Atefeh Ghahremanloo ◽  
Arash Soltani ◽  
Seyed Mohamad Sadegh Modaresi ◽  
Seyed Isaac Hashemy
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Clinical Development ◽  
Checkpoint Blockade ◽  
Recent Advances
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