PD-1/PD-L1 blockade in renal cell cancer

Beckermann, Kathryn E.; Johnson, Douglas B.; Sosman, Jeffrey A.

doi:10.1080/1744666x.2016.1214575

Cited by 31 publications

(17 citation statements)

References 54 publications

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“…Given the special mechanisms on effector immune cells and the late but durable response induced by immunotherapy, the conventionally evaluated criteria of Response Evaluation Criteria in Solid Tumors (RECIST) is not very accurate for the assessment of responses to PD-1/PD-L1 inhibitors. 6 Therefore, it is challenging but very important to distinguish the populations that most likely benefit from and to tell whether they truly response to these immune checkpoint blockade therapies at early stage of the treatment.…”

Section: Introductionmentioning

confidence: 99%

Dynamic change of PD-L1 expression on circulating tumor cells in advanced solid tumor patients undergoing PD-1 blockade therapy

et al. 2018

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Background: Tumor PD-L1 levels have predictive value in PD-1/PD-L1 checkpoint blockade therapies, yet biopsies can only provide baseline information. Whether PD-L1 expression on circulating tumor cells (CTCs) could serve as an alternative biomarker is of great interest.Design: We established an immunofluorescence assay for semi-quantitative assessment of the PD-L1 expression levels on CTCs with four categories (PD-L1negative, PD-L1low, PD-L1medium and PD-L1high). 35 patients with different advanced gastrointestinal tumors were enrolled in a phase 1 trial of a PD-1 inhibitor, IBI308. The CTC numeration and the PD-L1 expression levels were analyzed.Results: Prior the treatment of IBI308, 97% (34/35) patients had CTCs, ranging from1 to 70 (median 7). 74% (26/35) had PD-L1positive CTCs, and 60% (21/35) had at least one PD-L1high CTCs. The disease control (DC) rate in PD-L1high patients (48%) is much higher than the others (14%). The group with at least 20% abundance of PD-L1high CTCs had even higher DC rate of 64% (9/14), with only 14% DC rate for the rest (3/21). We also observed that the count changes of total CTC, PD-L1postive CTC and PD-L1high CTC correlate quite well with disease outcome (P<0.001, P = 0.002 and 0.007, respectively). In addition, the abundance of PD-L1high CTCs at baseline had predicative significance for progression free survival (PFS).Conclusions: We revealed that the abundance of PD-L1high CTCs at baseline might serve as a predictor to screen patients for PD-1/PD-L1 blockade therapies and measuring the dynamic changes of CTC could indicate the therapeutic response at early time.

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Section: Introductionmentioning

confidence: 99%

Dynamic change of PD-L1 expression on circulating tumor cells in advanced solid tumor patients undergoing PD-1 blockade therapy

et al. 2018

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“…Cancer immunotherapy triggers a patient’s immune system to destroy tumor cells by recognizing tumor-derived neoantigens [ 16 ][ 17 ]. Cancer immunotherapy drugs, such as checkpoint inhibitors, have improved the overall survival of patients with advanced stage cancers, particularly melanoma, non-small cell lung cancer, head and neck cancer and renal cancer [ 18 ][ 19 ][ 20 ]. Cytotoxic T cells recognize tumors as foreign because the latter express tumor-specific neoantigens derived from genetically altered proteins expressed by the tumor cells.…”

Section: Introductionmentioning

confidence: 99%

A neoepitope derived from a novel human germline APC gene mutation in familial adenomatous polyposis shows selective immunogenicity

Majumder

Shah²,

Elias

et al. 2018

PLoS ONE

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Familial adenomatous polyposis (FAP) is an inherited condition arising from genetic defects in the Adenomatous polyposis coli (APC) gene. Carriers with mutations in the APC gene develop polyps in the colon and rectum which if not managed, transition into colon cancer. In this study, we identified a novel germline mutation in the APC gene in members of an FAP-affected (Familial adenomatous polyposis) family. This unique heterozygous variant (c.735_736insT; p.Ser246PhefsTer6) was identified in ten out of twenty six family members, ranging in age from 6 to 60 years. Polyps were detected in six of the ten individuals (35–60 years) carrying this mutation. The remaining four members (6–23 years) remain polyp free. A significant fraction of FAP affected individuals eventually develop colon cancer and therapeutic interventions to prevent cancer progression remain elusive. To address this issue, we sought to determine if peptides derived from the novel APC mutation could induce a cytotoxic T cell response, thereby qualifying them as vaccine candidates. Peptides harboring the variant amino acids were first interrogated in silico for their immunogenicity using a proprietary neoepitope prioritization pipeline, OncoPeptVAC. A single 9-mer peptide was predicted to be immunogenic. Remarkably, CD8+ T cells isolated from either an FAP+/ APCmut individual, or from a FAP-/ APCmut individual, failed to respond to the peptide, whereas those from either an unaffected family member (FAP-/ APCwt) or from healthy unrelated donors, showed a robust response, suggesting that CD8+ T cells from individuals carrying this germline APC mutation have been tolerized to the mutation. Furthermore, experimental testing of six additional reported APC gene mutation-derived peptides revealed one of the six to be immunogenic. While not all APC mutant peptides are inmmunogenic, a few qualify as vaccine candidates offering novel treatment opportunities to patients with somatic APC gene mutations to delay/treat colorectal cancer.

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“…The biology that allows for a patient to respond to such therapy, however, is not fully understood. Kidney cancer has long been known to be resistant to traditional cytotoxic chemotherapy but can be responsive to immunotherapy (37). However, only 25% of RCC patients respond to treatment with single-agent monoclonal antibodies targeting PD-1, and approximately 40% respond with combined blockade of CTLA4 and PD-1 (27,28).…”

Section: Discussionmentioning

confidence: 99%

CD28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation

Beckermann¹,

Hongo²,

et al. 2020

JCI Insight

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PD-1/PD-L1 blockade in renal cell cancer

Cited by 31 publications

References 54 publications

Dynamic change of PD-L1 expression on circulating tumor cells in advanced solid tumor patients undergoing PD-1 blockade therapy

Dynamic change of PD-L1 expression on circulating tumor cells in advanced solid tumor patients undergoing PD-1 blockade therapy

A neoepitope derived from a novel human germline APC gene mutation in familial adenomatous polyposis shows selective immunogenicity

CD28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation

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