Safety and activity of autologous T cells with enhanced NY-ESO-1–specific T-cell receptor (GSK3377794) in HLA-a*02+ previously-treated and -untreated patients with advanced metastatic/unresectable synovial sarcoma: A master protocol study design (IGNYTE-ESO).

TPS11571 Background: T cells modified to target NY-ESO-1 have shown encouraging activity in HLA-A*02+ patients with NY-ESO-1–positive synovial sarcoma. NY-ESO-1 is a cancer/testis antigen that is expressed across multiple tumor types and highly expressed in synovial sarcoma. NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR able to recognize NY-ESO-1 epitope in complex with HLA-A*02. Ongoing trials are evaluating GSK3377794 in multiple solid tumors and multiple myeloma. Methods: This study (NCT03967223) uses a Master Protocol design that allows investigation of GSK3377794 in multiple tumor types under the same protocol in separate substudies. The first two are single-arm substudies in patients with advanced metastatic or unresectable synovial sarcoma: treatment-naïve (1st line [1L], substudy 1; n = 10 planned) and progressing after anthracycline-based chemotherapy (2L+, substudy 2; n = 55 planned). Patients must be aged ≥10 years, have adequate organ function, ECOG performance status 0–1, measurable disease, and no central nervous system metastases. Excluded prior treatments include gene therapy with an integrating vector or NY-ESO-1–specific T cells, vaccine or targeting antibody, or allogeneic stem cell transplant. Patients will undergo leukapheresis and manufacture of GSK3377794; lymphodepletion then GSK3377794 infusion, followed by safety and disease assessments; and long-term follow-up for 15 years (under a separate protocol). The primary objective of substudy 2 is overall response rate per RECIST v1.1 by central independent review. Secondary objectives include time to response, duration of response, disease control rate, progression-free survival, overall survival, plus safety and tolerability. Exploratory objectives include assessment of the correlation of T-cell persistence with safety, clinical responses, and infused T-cell phenotype. Evaluation of quality of life and daily functioning of patients will also be assessed. Enrollment began in December 2019. These data are presented on behalf of the original authors with their permission. A similar presentation (P453) was presented at the SITC Annual Meeting, National Harbor, MD, USA, Nov 6–10, 2019. Funding: GlaxoSmithKline (208467) Clinical trial information: NCT03967223 .

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IGNYTE-ESO: A master protocol to assess safety and activity of letetresgene autoleucel (lete-cel; GSK3377794) in HLA-A*02+ patients with synovial sarcoma or myxoid/round cell liposarcoma (Substudies 1 and 2).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps11582 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS11582-TPS11582

Author(s):

Sandra P. D'Angelo ◽

Jonathan Christopher Noujaim ◽

Fiona Thistlethwaite ◽

Albiruni Ryan Abdul Razak ◽

Silvia Stacchiotti ◽

...

Keyword(s):

T Cell ◽

Clin Oncol ◽

Synovial Sarcoma ◽

Specific Gene ◽

Type I ◽

Cell Transplant ◽

Round Cell ◽

Multiple Tumor ◽

Anthracycline Therapy ◽

Tumor Types

TPS11582 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell product using a genetically modified T-cell receptor to target cancer cells expressing the cancer testis antigen New-York esophageal squamous cell carcinoma 1 (NY-ESO-1). Lete-cel is currently being investigated alone and in combination in multiple tumor types [1,2]. NY-ESO-1 is expressed in 70‒80% of synovial sarcoma (SS) and 80‒90% of myxoid/round cell liposarcoma (MRCLS) tumors [3,4], suggesting these tumors may be prime lete-cel targets. This master protocol design (IGNYTE-ESO; NCT03967223) enables evaluation of multiple cell therapies in multiple tumor types and treatment stages in separate substudies, beginning with lete-cel in Substudies 1 and 2 for SS and MRCLS. Methods: Substudy 1 is a single-arm study assessing lete-cel in treatment-naïve patients (pts; ie, anthracycline therapy-naïve for metastatic disease) with advanced (metastatic/unresectable) NY-ESO-1+ SS or MRCLS as a first line of therapy (n=10 planned). Substudy 2 is a pivotal, single-arm study assessing lete-cel in pts with NY-ESO-1+ SS or MRCLS who progressed after anthracycline therapy (n=70 planned). Key eligibility criteria are age ≥10 y and NY-ESO-1 and HLA-A*02 positivity. Exclusion criteria include prior NY-ESO-1–specific/gene therapy, allogeneic stem cell transplant, and central nervous system metastases. Screened pts undergo leukapheresis for lete-cel manufacture, lymphodepletion, lete-cel infusion, and follow-up (FU). Long-term FU (15 y) may be done under a separate protocol. The Substudy 2 primary endpoint is overall response rate (ORR) per RECIST v1.1 assessed by central independent review. Substudy 1 is not testing any formal hypotheses; statistical analysis will be descriptive. Substudy 2 is comparing ORR with the historical control assuming at least 90% power with 0.025 one-sided type I error. Secondary endpoints include efficacy (time to/duration of response, disease control rate, progression-free survival), safety (adverse event [AE] frequency/severity, serious AEs, AEs of special interest), and pharmacokinetic (maximum transgene expansion [Cmax], time to Cmax, area under the time curve from zero to time t as data permit). Enrollment began in December 2019. References: 1. Reckamp KL, et al. Ann Oncol 2019;30(Suppl_5):v602–v660. 2. Rapoport A, et al. J Clin Oncol 2020 38:15_suppl, TPS8555. 3. D’Angelo SP, et al. Cancer Discov 2018;8(8):944–957. 4. D’Angelo SP, et al. J Clin Oncol 2018 36:15_suppl, 3005. Funding: GSK. Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Previously presented at BSG 2021 (P914542). Clinical trial information: NCT03967223.

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Phenotypic Differences of CD103+ Tissue-Resident Memory T Cells Associated with Various Cancers

Pathobiology ◽

10.1159/000518972 ◽

2021 ◽

pp. 1-11

Author(s):

Hye Seon Park ◽

Yeonjin Jeon ◽

Hyun Lee ◽

Heejae Lee ◽

Young-Ae Kim ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Clinical Importance ◽

Effector Memory ◽

Cell Phenotype ◽

Clinicopathologic Characteristics ◽

Phenotypic Differences ◽

Cancer Types ◽

Tumor Types ◽

Resident Memory T Cells

Background/Aims: The presence and clinical importance of tissue-resident memory T (TRM) cells have been recently described in association with various cancer types. However, the frequency and the traditional naïve–effector–memory phenotypic characteristics of TRM cells are largely unknown. Methods: We analyzed single-cell populations of colorectal cancer (CC, n = 18), stomach cancer (SC, n = 13), renal cell carcinoma (RCC, n = 19), and breast cancer (BC, n = 16) by dissociation of tumor tissue with collagenase/hyaluronidase. We investigated populations of naïve, effector, and memory T and TRM cells by flow cytometry. Results: Among CD8− cells, CC was associated with a significantly higher proportion of CD103+ T cells than other tumor types (p < 0.001). Among CD8+ cells, CC and SC were associated with higher CD103+ T-cell proportions than RCC and BC (p < 0.001). Significantly more CD8+ than CD8− cells expressed CD103 (p < 0.001). In association with SC, RCC, and BC, CD8+ T cells had a similar T-cell phenotype composition pattern: fewer effector T cells and more memory-type T cells among CD103+ cells compared with CD103− cells (p < 0.05). Tumors with higher proportion of CD103+ cells had no specific clinicopathologic characteristics than those with lower proportion of CD103+ cells. Conclusion: TRM cell abundance and phenotypes varied among CC, SC, RCC, and BC. Further studies regarding the functional differences of TRM associated with various tumors are warranted.

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Cytotoxic T-lymphocyte-associated Protein 4 and Cancer Therapy

Blood ◽

10.1182/blood.v126.23.sci-7.sci-7 ◽

2015 ◽

Vol 126 (23) ◽

pp. SCI-7-SCI-7

Author(s):

James Allison

Keyword(s):

T Cells ◽

T Cell ◽

Cancer Therapy ◽

Mouse Models ◽

Late Stage ◽

Cd4 T Cells ◽

Controlled Trial ◽

Immune Checkpoints ◽

Multiple Tumor ◽

Tumor Types

Abstract The existence of multiple non-redundant l inhibitory pathways that limit T cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits CD28 mediated costimulation. Antibodies to CTLA-4 have proven effective against multiple tumor types in both pre-clinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long term (>4.5 years) survival benefit in about 23% of patients in a randomized, placebo-controlled trial in late stage melanoma. In 2011 it was approved by the FDA for treatment of late stage melanoma and is now a standard of care for that disease. A recent retrospective study of almost 5,000 patients showed an inflection point at about 2.5 years with essentially no deaths of about 20% of patients for 10 years following treatment. The mechanism(s) of action of anti-CTLA-4 are still being elucidated. We and others have shown that CLTA-4 limits T cell proliferation by a cell intrinsic mechanism. However, there is also evidence that anti-CTLA-4 has to engage the target on both effector (Teff) and regulatory (Treg) T cells. We have recently uncovered a mechanism whereby anti-CTLA-4 antibodies expand Treg in lymph nodes but cause their depletion in the tumor microenvironment. Thus anti-CTLA-4 exerts its anti-tumor effects by multiple mechanisms. We have also shown that CTLA-4 blockade results in a 2-5 fold increase in the frequency of CD4 T cells expression ICOS (inducible costimulator) in both tumor tissues and blood. This population contains that vast majority of tumor antigen specific cells that produce IFNg and TNFa. The appearance of the ICOS+ CD4 cells serves as a pharmacodynamic marker of a biological effect of anti-CTLA-4 activity. Using mouse models, we have shown that the ICOS/ICOSL pathway is critical for optimal anti-tumor activity of anti-CTLA-4. Furthermore, we have shown that agonist stimulation of ICOS coupled with CTLA-4 blockade results in enhanced anti-tumor efficacy in mouse models, suggest that ICOS is a compelling molecule to develop as a target for agonistic targeting of costimulatory checkpoints. PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T cell antigen receptor mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25% . A recent phase II trial of a combination of anti-PD-1 and anti-CTLA-4 in melanoma showed objective responses in about 50% of late stage melanoma patients. Our studies indicate that the mechanisms of anti-PD-1 mediated tumor immunity are distinct from those of anti-CTLA-4, at least as for the role of ICOS+ CD4 T cells. These studies and their implications for cancer therapy will be discussed. Disclosures Allison: Jounce Therapeutics: Consultancy, Equity Ownership, Patents & Royalties: Licensed patent.; Bristol Meyers-Squibb: Patents & Royalties: Licensed patent owned by the University of California. Previously received royalties.

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Clinical and pharmacodynamic (PD) results of a phase I trial with AMP-224 (B7-DC Fc) that binds to the PD-1 receptor.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3044 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3044-3044 ◽

Cited By ~ 15

Author(s):

Jeffrey R. Infante ◽

John D. Powderly ◽

Howard A. Burris ◽

Muaiad Kittaneh ◽

Jessica Houston Grice ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Response ◽

Tumor Immune Evasion ◽

Effector Cells ◽

Multiple Tumor ◽

Infusion Reactions ◽

Pre Treatment ◽

Tumor Types ◽

Blocking Antibodies

3044 Background: PD-1/B7-H1 (PD-L1) axis blockade can reinvigorate T cells, and overcome tumor immune evasion of multiple tumor types. AMP-224 is the first recombinant B7-DC-Fc fusion protein tested in patients that binds to and modulates the PD-1 axis through a unique MOA. The MoA hypothesis for AMP-224 is depletion of PD-1high expressing T-cells representing exhausted effector cells. Subsequent replenishment of the T-cell pool with functional T-cells may restore immune function. Methods: Patients with advanced solid tumors received low dose CTX on Day 0, followed by AMP-224 (IV infusion) on Days 1 and 15 of each 28-day cycle in doses ranging from 0.3 to 30 mg/kg. Blood samples were assessed serially for changes in lymphocyte subsets, PD-1HIT cells and T cell effector function. IHC staining of paired biopsies for B7-H1, CD8, PD-1, CD4 and FoxP3 was performed to assess immunological status of the tumor at baseline and following treatment and then relative to peripheral readouts. Results: 42 patients (83% melanoma) were treated with varying doses of AMP-224 [0.3 mg/kg (n = 6); 1 mg/kg (n=4); 3 mg/kg (n = 4); 10 mg/kg (n = 22); 30 mg/kg (n = 6)]. Infusion reactions were common (69% across dose cohorts) and occurred mostly at higher doses (86% at the 10 mg/kg dose). No drug-related inflammatory adverse events were identified contrary to PD-1 blocking antibodies. Fresh pre-treatment biopsies were collected from 33/42 (78.5%) patients and paired biopsies have been collected thus far from 19/36 (52.7%) patients on study. 31% of baseline tumors were B7-H1+. Several PD readouts in the periphery showed reductions in PD-1HIcells and emergence of a functional T cell response (increases in IFNg+, TNFa+, IL-2+ CD4 and CD8 T cells) in individual patients where partial response, stable disease, and mixed responses were seen. Conclusions: Data from peripheral readouts is consistent with hypothesized AMP-224 MoA. B7-H1+ was not always predictive of functional response to AMP-224 immunotherapy. Comprehensive PD readouts and evaluation of PK/PD relationships will be presented and may ultimately predict restoration of immune competence even in the presence of initial disease progression. Clinical trial information: NCT01352884.

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The Impact of Exercise Serum on Selected Parameters of CD4+ T Cell Metabolism

Immuno ◽

10.3390/immuno1030008 ◽

2021 ◽

Vol 1 (3) ◽

pp. 119-131

Author(s):

Jana Palmowski ◽

Kristina Gebhardt ◽

Thomas Reichel ◽

Torsten Frech ◽

Robert Ringseis ◽

...

Keyword(s):

T Cells ◽

Oxygen Consumption ◽

T Cell ◽

Real Time ◽

Cd4 T Cells ◽

Cell Metabolism ◽

Cd4 T Cell ◽

Autologous Serum ◽

Cell Phenotype ◽

The Impact

CD4+ T cells are sensitive to peripheral changes of cytokine levels and metabolic substrates such as glucose and lactate. This study aimed to analyze whether factors released after exercise alter parameters of human T cell metabolism, specifically glycolysis and oxidative phosphorylation. We used primary human CD4+ T cells activated in the presence of autologous serum, which was collected before (CO) and after a 30-min exercise intervention (EX). In the course of activation, cells and supernatants were analyzed for cell viability and diameter, real-time oxygen consumption by using PreSens Technology, mRNA expression of glycolytic enzymes and complexes of the electron transport chain by real-time PCR, glucose, and lactate levels in supernatants, and in vitro differentiation by flow cytometry. EX did not alter T cell phenotype, viability, or on-blast formation. Similarly, no difference between CO and EX were found for CD4+ T cell activation and cellular oxygen consumption. In contrast, higher levels of glucose were found after 48 h activation in EX conditions. T cells activated in autologous exercise serum expressed lower HK1 mRNA and higher IFN-γ receptor 1. We suggest that the exercise protocol used was not sufficient to destabilize the immune metabolism of T cells. Therefore, more intense and prolonged exercise should be used in future studies.

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PTEN loss correlates with T cell exclusion across human cancers

BMC Cancer ◽

10.1186/s12885-021-08114-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ziying Lin ◽

Lixia Huang ◽

Shao Li Li ◽

Jincui Gu ◽

Xiaoxian Cui ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Helper Cells ◽

Pi3k Pathway ◽

T Helper ◽

Immune Microenvironment ◽

Pten Loss ◽

Pathway Activation ◽

Tumor Types ◽

T Cell Exclusion

Abstract Background Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood. Methods Utilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation. Results We reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy. Conclusion These data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.

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Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small-molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (I-O) drugs.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2506 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2506-2506

Author(s):

Anthony W. Tolcher ◽

James Andrew Reeves ◽

Meredith McKean ◽

Bartosz Chmielowski ◽

Joseph Thaddeus Beck ◽

...

Keyword(s):

Metastatic Melanoma ◽

Solid Tumors ◽

Phase Ii ◽

Phase Ii Study ◽

Performance Status ◽

Nerve Sheath Tumor ◽

Advanced Solid Tumors ◽

Antitumor Effects ◽

Ecog Performance Status ◽

Multiple Tumor

2506 Background: Alrizomadlin (APG-115) restores TP53 function, activating p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. Alrizomadlin also functions as a host immunomodulator and hence may restore antitumor activity in pts with cancers failing PD-1/PD-L1 blockade. Methods: This US multicenter trial assessed alrizomadlin combined with pembrolizumab in pts with unresectable/metastatic melanoma or advanced solid tumors that had failed I-O drugs; or pts with malignant peripheral nerve sheath tumor (MPNST), liposarcoma, or ATM mutant solid tumors that had failed any standard therapy. Eligible pts had ECOG performance status of 0-2 and no CNS metastases. The phase II study cohorts included pts with melanoma, NSCLC, solid tumor with ATM mutation, well-differentiated/dedifferentiated liposarcoma, urothelial carcinoma, and MPNST. Alrizomadlin was administered orally at 150 mg once every other day for 2 consecutive weeks with 1 week off and pembrolizumab at 200 mg via IV infusion for 30 minutes on Day 1 of a 21-day cycle. Results: As of December 25, 2020, 84 pts had been treated in 6 cohorts: melanoma (n = 26), NSCLC (n = 23), ATM mutation (n = 9), liposarcoma (n = 14), urothelial (n = 9), and MPNST (n = 3). In the PD-1/PD-L1 inhibitor-failed melanoma cohort, there was 1 confirmed partial response (PR) out of 5 pts with uveal melanoma, 2 PR (1 confirmed and 1 unconfirmed) of 5 pts with mucosal melanoma, and 1 confirmed PR of 11 pts with cutaneous melanoma. ORR in the melanoma cohort was 17.4% (4/23 evaluable pts), and the disease control rate was 60.9% (14/23). In the MPNST cohort, 1 of 3 pts had an unconfirmed ongoing PR. In I-O drug-failed NSCLC (n = 14 evaluable) and urothelial (n = 5 evaluable) cohorts, each reported 1 confirmed PR. Common treatment (alrizomadlin or pembrolizumab)-related adverse events (TRAEs) (≥ 10%) were nausea (63.1%), thrombocytopenia (36.9%), vomiting (33.3%), fatigue (31.0%), decreased appetite (27.4%), diarrhea (21.4%), neutropenia (15.4%), and anemia (11.9%). Grade ≥ 3 TRAEs (≥ 5%) included thrombocytopenia (20.2%), neutropenia (14.2%), and anemia (8.3%). Eleven pts discontinued treatment due to AEs: 5 were treatment related, including 2 grade 4 thrombocytopenia, and 1 each of grade 2 vomiting, grade 2 fatigue, and grade 2 posterior reversible encephalopathy syndrome (PRES). Three treatment-related SAEs were PRES, pyrexia, and asthenia. Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and may restore antitumor effects in pts with cancer resistant to or intolerant of I-O drugs, as suggested by preliminary antitumor activities in multiple tumor types. Internal study identifiers: APG-115-US-002; Keynote MK-3475-B66. Clinical trial information: NCT03611868.

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Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8+T cell dysfunction and maintain memory phenotype

Science Immunology ◽

10.1126/sciimmunol.aat7061 ◽

2018 ◽

Vol 3 (29) ◽

pp. eaat7061 ◽

Cited By ~ 44

Author(s):

Bei Wang ◽

Wen Zhang ◽

Vladimir Jankovic ◽

Jacquelynn Golubov ◽

Patrick Poon ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Cancer Immunotherapy ◽

Effector Memory ◽

Cell Phenotype ◽

Checkpoint Inhibition ◽

Cell Dysfunction ◽

T Cell Dysfunction

Most patients with cancer do not develop durable antitumor responses after programmed cell death protein 1 (PD-1) or programmed cell death ligand 1(PD-L1) checkpoint inhibition monotherapy because of an ephemeral reversal of T cell dysfunction and failure to promote long-lasting immunological T cell memory. Activating costimulatory pathways to induce stronger T cell activation may improve the efficacy of checkpoint inhibition and lead to durable antitumor responses. We performed single-cell RNA sequencing of more than 2000 tumor-infiltrating CD8+T cells in mice receiving both PD-1 and GITR (glucocorticoid-induced tumor necrosis factor receptor–related protein) antibodies and found that this combination synergistically enhanced the effector function of expanded CD8+T cells by restoring the balance of key homeostatic regulators CD226 and T cell immunoreceptor with Ig and ITIM domains (TIGIT), leading to a robust survival benefit. Combination therapy decreased CD8+T cell dysfunction and induced a highly proliferative precursor effector memory T cell phenotype in a CD226-dependent manner. PD-1 inhibition rescued CD226 activity by preventing PD-1–Src homology region 2 (SHP2) dephosphophorylation of the CD226 intracellular domain, whereas GITR agonism decreased TIGIT expression. Unmasking the molecular pathways driving durable antitumor responses will be essential to the development of rational approaches to optimizing cancer immunotherapy.

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Current Strategies for Identification of Glioma Stem Cells: Adequate or Unsatisfactory?

Journal of Oncology ◽

10.1155/2012/376894 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 44

Author(s):

Paola Brescia ◽

Cristina Richichi ◽

Giuliana Pelicci

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Large Scale ◽

Molecular Mechanisms ◽

Cell Phenotype ◽

Multiple Tumor ◽

Early Results ◽

Tumorigenic Potential ◽

Tumor Types

Cancer stem cells (CSCs) were isolated in multiple tumor types, including human glioblastomas, and although the presence of surface markers selectively expressed on CSCs can be used to isolate them, no marker/pattern of markers are sufficiently robust to definitively identify stem cells in tumors. Several markers were evaluated for their prognostic value with promising early results, however none of them was proven to be clinically useful in large-scale studies, leading to outstanding efforts to identify new markers. Given the heterogeneity of human glioblastomas further investigations are necessary to identify both cancer stem cell-specific markers and the molecular mechanisms sustaining the tumorigenic potential of these cells to develop tailored treatments. Markers for glioblastoma stem cells such as CD133, CD15, integrin-α6, L1CAM might be informative to identify these cells but cannot be conclusively linked to a stem cell phenotype. Overlap of expression, functional state and morphology of different subpopulations lead to carefully consider the techniques employed so far to isolate these cells. Due to a dearth of methods and markers reliably identifying the candidate cancer stem cells, the isolation/enrichment of cancer stem cells to be therapeutically targeted remains a major challenge.

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P09.05 Plasma CD27, a surrogate of intratumoral CD27-CD70 interaction, correlates with immunotherapy resistance in renal cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-itoc8.55 ◽

2021 ◽

Vol 9 (Suppl 1) ◽

pp. A30.1-A30

Author(s):

N Benhamouda ◽

I Sam ◽

N Epaillard ◽

A Gey ◽

A Saldmann ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Single Cell ◽

Solid Tumors ◽

Tumor Cells ◽

Principal Investigator ◽

Cell Phenotype ◽

Metastatic Rcc ◽

Research Grant

BackgroundCD70, a costimulatory molecule on antigen presenting cells, is known to activate CD27-expressing T cells. CD27-CD70 interaction leads to the release of soluble CD27 (sCD27). However, persistent interaction of CD27 and CD70 such as in chronic infection may exhaust the T cell pool and promote apoptosis. Surprisingly, our analysis based on TCGA database show that clear cell renal cell carcinoma (ccRCC) expresses the highest levels of CD70 among all solid tumors. Despite the important clinical efficacy of immunotherapy by anti-PD-1 in RCC patients, the overall response to anti-PD1 remains modest. The relationship between the CD27-CD70 interaction in the RCC and the response to immunotherapy is still unclear.Materials and MethodsTo study the CD27 and CD70 expression in the tumor microenvironment (TME), FFPE tumor tissues from 25 RCC patients were analysed using multiplex in situ immunofluorescence. 10 fresh RCC tumor samples were collected to analyse the phenotype of CD27+ T cells by flow cytometry and 4 samples were proceeded for single-cell RNA-seq analysis. A cohort of metastatic RCC patients (n = 35) treated by anti-PD-1 were enrolled for the measurement of plasma sCD27 by ELISA and the survival analysis is also realized.ResultsIn the TME, we demonstrated that CD27+ T cells interact with CD70-expressing tumor cells. In fresh tumors from RCC patients, CD27+ T cells express higher levels of cleaved caspase 3 (a classical marker of apoptosis) than CD27- T cells. We confirmed the apoptotic signature (BAX, FASLG, BCL2L11, CYCS, FBXO32, LGALS1, PIK3R1, TERF1, TXNIP, CDKN2A) of CD27+ T cells by single-cell RNAseq analysis. CD27+T cells also had a tissue resident memory T cell phenotype with enriched gene expression of ITGAE, PRDM1, RBPJ and ZNF683. Moreover, CD27+T cells display an exhaustion phenotype with the expression of multiple inhibitory receptors gene signature (PDCD1, CTLA4, HAVCR2, LAG3, etc). Besides, intratumoral CD27-CD70 interaction significantly correlates with plasma sCD27 concentration in RCC (p = 0.0017). In metastatic RCC patients treated with anti-PD-1, higher levels of sCD27 predict poor overall survival (p = 0.037), while it did not correlate with inflammatory markers or clinical prognostic criteria.ConclusionsIn conclusion, we demonstrated that sCD27, a surrogate of T cell dysfunction in tumors likely induced by persistent interactions of CD27+T cells and CD70-expressing tumor cells, is a predictive biomarker of resistance to immunotherapy in mRCC. To our knowledge, this is the first report showing that a peripheral blood biomarker may reflect certain aspects of the tumor-host interaction in the tumor microenvironment. Given the frequent expression of CD70 and CD27 in solid tumors, our findings may be further extended to other types of tumors. CD70-CD27 interaction could thus be considered as a mechanism of tumor escape, but also a novel therapeutic target in cancers.Disclosure InformationN. Benhamouda: None. I. Sam: None. N. Epaillard: None. A. Gey: None. A. Saldmann: None. J. Pineau: None. M. Hasan: None. V. Verkarre: None. V. Libri: None. S. Mella: None. C. Granier: None. C. Broudin: None. P. Ravel: None. B. Jabla: None. N. Chaput: None. L. Albiges: None. Y. Vano: None. O. Adotevi: None. S. Oudard: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; SIRIC CARPEM, FONCER. E. Tartour: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Fondation ARC, INCA PLBio, Labex Immuno-Oncology, SIRIC CARPEM, FONCER, IDEX université de Paris, Inserm Transfert.

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