High expression of carcinoembryonic antigen and telomerase reverse transcriptase in circulating tumor cells is associated with poor clinical response to the immune checkpoint inhibitor nivolumab

36 Background: Selection of Immune Checkpoint Inhibitor (ICI) therapies in Head and Neck cancers are based on IHC based detection of PD-L1 expression in tumor tissue. Invasive biopsy to obtain tumor tissue for IHC is associated with procedural risks, sequelae and expenses. Prior efforts at PD-L1 profiling of Circulating Tumor Cells (CTCs) have been constrained by low CTC yields. We employed a novel approach for harvesting sufficient CTCs from Head and Neck cancers that permit PD-L1 profiling by Immunocytochemistry (ICC). Methods: 15 ml peripheral blood was collected from 95 patients with head and neck squamous cell carcinomas (HNSCC). CTCs were enriched from PBMCs via an epigenetically acting stabilization process which induced apoptosis in non-malignant cells and conferred survival privilege on apoptosis-resistant CTCs, which were harvested and confirmed by immunostaining for EpCAM and pan-CK. Deep ICC profiling of CTCs was performed with organ-specific markers as well as PD-L1:22c3 and PD-L1:28-8 clones. Results: Viable CTCs could be enriched and harvested in 90 out of 95 samples (95.3%) regardless of metastatic or treatment status. Deep ICC and PD-L1 profiling could be performed in all 90 samples (100%). PD-L1 expression was quantitatively assigned as ‘Low’, ‘Moderate’ or ‘High’. 28 (31.1%) samples were positive for PD-L1:28-8 (27 Low + 1 Moderate) and 26 (28.9%) samples were positive for PD-L1:22c3 (24 Low + 2 Moderate). 15 samples were positive for both PD-L1 clones. Conclusions: CTCs in Head and Neck squamous cell carcinomas can be considered for evaluating PD-L1 expression in patients where ICI therapies are otherwise viable.

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PD-L1 profiling of circulating tumor cells for immune checkpoint inhibitor therapy in gastroesophageal cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.29 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 29-29

Author(s):

Pradip Devhare ◽

Revati Patil ◽

Dadasaheb B. Akolkar ◽

Darshana Patil ◽

Navin Srivastava ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Tumor Tissue ◽

Checkpoint Inhibitor ◽

Novel Approach ◽

Organ Specific ◽

Induced Apoptosis ◽

Esophageal Carcinomas

29 Background: Selection of Immune Checkpoint Inhibitor (ICI) therapies in Gastroesophageal cancers are based on IHC based detection of PD-L1 expression in tumor tissue. Invasive biopsy to obtain tumor tissue for IHC is associated with procedural risks, sequelae and expenses. Prior efforts at PD-L1 profiling of Circulating Tumor Cells (CTCs) have been constrained by low CTC yields. We employed a novel approach for harvesting sufficient CTCs from Gastroesophageal cancers that permit PD-L1 profiling by Immunocytochemistry (ICC). Methods: 15 ml peripheral blood was collected from 106 patients among whom 20 were diagnosed with gastric adenocarcinomas (AD) and 86 with either esophageal AD or esophageal squamous cell carcinomas (SCC). CTCs were enriched from PBMCs via an epigenetically acting stabilization process which induced apoptosis in non-malignant cells and conferred survival privilege on apoptosis-resistant CTCs, which were harvested and confirmed by immunostaining for EpCAM and pan-CK positivity. Deep ICC profiling of CTCs was performed with organ-specific markers as well as PD-L1:22c3 and PD-L1:28-8 clones. Results: Viable CTCs could be enriched and harvested in 103 out of 106 samples (97.2%) regardless of metastatic or treatment status. Deep ICC and PD-L1 profiling could be performed in all 103 samples (100%). PD-L1 expression was quantitatively assigned as ‘Low’, ‘Moderate’ or ‘High’. Among the 19 gastric ADs, 5 (26.3%) samples were positive for PD-L1:22c3 and 2 (10.5%) were positive for PD-L1:28-8; all gastric ADs were ‘Low’ for either PD-L1 subtype. Among the 84 esophageal carcinomas (AD+SCC), 32 samples (38.1%) were positive for PD-L1:22c3 (26 Low + 5 Moderate + 1 High) and 16 (19.1%) were positive for PD-L1:28-8 (11 Low + 5 Moderate). Conclusions: CTCs in Gastroesophageal cancers can be considered for evaluating PD-L1 expression in patients where ICI therapies are otherwise viable.

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Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002181 ◽

2021 ◽

Vol 9 (6) ◽

pp. e002181

Author(s):

Erin F Simonds ◽

Edbert D Lu ◽

Oscar Badillo ◽

Shokoufeh Karimi ◽

Eric V Liu ◽

...

Keyword(s):

T Cells ◽

Tumor Cells ◽

Immune Evasion ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Prolonged Survival ◽

Tumor Associated Macrophages ◽

The Brain ◽

Immune Profiling

BackgroundGlioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed.MethodsWe used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations.ResultsICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation.ConclusionsOur data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.

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A phase 1 dose-escalation trial of intratumoral TTI-621, a novel immune checkpoint inhibitor targeting CD47, in subjects with relapsed or refractory percutaneously-accessible solid tumors and mycosis fungoides.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps3101 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS3101-TPS3101 ◽

Cited By ~ 1

Author(s):

John A. Thompson ◽

Oleg Akilov ◽

Christiane Querfeld ◽

Matthew H. Taylor ◽

Lisa Johnson ◽

...

Keyword(s):

Antitumor Activity ◽

Solid Tumors ◽

Tumor Cells ◽

Mycosis Fungoides ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Phase 1 ◽

Macrophage Phagocytosis ◽

The Impact

TPS3101 Background: CD47 is an immune checkpoint that binds to signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Tumor cells frequently overexpress CD47 and exploit this pathway to evade macrophage-mediated destruction. CD47 blockade promotes both innate (macrophage phagocytosis) and adaptive immunity (T cell responses). TTI-621 (SIRPαFc) is an immune checkpoint inhibitor designed to bind human CD47 and block the “do not eat” signal. The IgG1 region of TTI-621 engages Fcγ receptors on macrophages, converting the inhibitory signal to one that activates, thereby enhancing phagocytosis, and antitumor activity. A Phase 1 study is ongoing to evaluate the safety/tolerability and preliminary efficacy of IV administered TTI-621 in subjects with relapsed/refractory hematologic malignancies. It is hypothesized that employing direct intratumoral injections will result in very high local target engagement, promoting the development of innate and adaptive immune responses. Methods: A Phase 1 multicenter, open-label study was initiated to characterize the safety and tolerability of delivering TTI-621 directly into cancer lesions to achieve high local CD47 engagement to increase phagocytosis of tumor cells (NCT02890368). Subjects are being enrolled in sequential cohorts that gradually increase in dose and dosing frequency to characterize the feasibility of intratumoral TTI-621 injections and their safety, PK, pharmacodynamics, and preliminary antitumor activity. Eligible subjects are adults with relapsed or refractory percutaneously-accessible solid tumors or mycosis fungoides (MF), which have progressed on standard anticancer therapy or for which no other approved therapy exists. TTI-621 is delivered by intratumoral injection at protocol-defined doses and dosing regimens starting at 1 mg/injection. Serial biopsies are being collected to characterize local anti-tumor responses and assess the impact of TTI-621 on the tumor microenvironment. Clinical trial information: NCT02890368.

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