Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

Lawrence P. Andrews; Ashwin Somasundaram; Jessica M. Moskovitz; Andrea L. Szymczak-Workman; Chang Liu; Anthony R. Cillo; Huang Lin; Daniel P. Normolle; Kelly D. Moynihan; Ichiro Taniuchi; Darrell J. Irvine; John M. Kirkwood; Evan J. Lipson; Robert L. Ferris; Tullia C. Bruno; Creg J. Workman; Dario A. A. Vignali

doi:10.1126/sciimmunol.abc2728

Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

Science Immunology ◽

10.1126/sciimmunol.abc2728 ◽

2020 ◽

Vol 5 (49) ◽

pp. eabc2728 ◽

Cited By ~ 2

Author(s):

Lawrence P. Andrews ◽

Ashwin Somasundaram ◽

Jessica M. Moskovitz ◽

Andrea L. Szymczak-Workman ◽

Chang Liu ◽

...

Keyword(s):

Resistance Mechanism ◽

Lymphocyte Activation ◽

Inverse Correlation ◽

Standard Of Care ◽

Skin Cancers ◽

Adam10 Expression ◽

Patient Responsiveness ◽

Pd1 Blockade ◽

Response Expression ◽

T Cell Help

Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte activation gene–3 (LAG3) signaling is regulated by a disintegrin and metalloprotease domain-containing protein–10 (ADAM10)– and ADAM17-mediated cell surface shedding. Here, we show that mice expressing a metalloprotease-resistant, noncleavable LAG3 mutant (LAG3NC) are resistant to PD1 blockade and fail to mount an effective antitumor immune response. Expression of LAG3NC intrinsically perturbs CD4+ T conventional cells (Tconvs), limiting their capacity to provide CD8+ T cell help. Furthermore, the translational relevance for these observations is highlighted with an inverse correlation between high LAG3 and low ADAM10 expression on CD4+ Tconvs in the peripheral blood of patients with head and neck squamous cell carcinoma, which corresponded with poor prognosis. This correlation was also observed in a cohort of patients with skin cancers and was associated with increased disease progression after standard-of-care immunotherapy. These data suggest that subtle changes in LAG3 inhibitory receptor signaling can act as a resistance mechanism with a substantive effect on patient responsiveness to immunotherapy.

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Metabolomic adaptations and correlates of survival to immune checkpoint blockade

Nature Communications ◽

10.1038/s41467-019-12361-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 30

Author(s):

Haoxin Li ◽

Kevin Bullock ◽

Carino Gurjao ◽

David Braun ◽

Sachet A. Shukla ◽

...

Keyword(s):

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Resistance Mechanism ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Adaptive Resistance ◽

Metabolic Monitoring ◽

Pd1 Blockade ◽

To Receive ◽

Cell Death Protein

Abstract Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase (IDO/TDO) inhibitors.

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EXTH-29. DUAL TGFB AND PD1 BLOCKADE PROMOTES GERMINAL-CENTER B-CELL IMMUNE RESPONSES AGAINST GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.668 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi169-vi169

Author(s):

Mark Dapash ◽

David Hou ◽

Brandyn Castro ◽

Aida Rashidi ◽

Peng Zhang ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Standard Of Care ◽

Current Standard ◽

Term Survival ◽

Therapeutic Benefits ◽

Immunosuppressive Cytokine ◽

Pd1 Blockade ◽

Tgfb Signaling

Abstract In contrast to other malignancies such as melanoma and sarcoma, Glioblastoma (GBM) remains difficult to treat with immunotherapies. Recent studies have shown that positive immunotherapeutic responses are mediated by the accumulation of germinal-center-like B cells which are predictive of survival in patients treated with neoadjuvant PD1 blockade. In contrast, GBM-associated B-cells are scarce and the establishment of germinal-center like cells have not been observed. This study seeks to identify how B-cells are driven towards their immunosuppressive phenotypes in GBM and how this prevents immunotherapeutic efficacy. Utilizing single-cell RNA sequencing (scRNA-seq) in a CT2A murine glioma model, TGFb receptors 1 and 3 were identified as the most highly expressed inhibitory receptors on GBM-associated B cells. Furthermore, using scRNA-seq, TGFb1 was identified as the most highly expressed immunosuppressive cytokine in the TME, which was produced principally by tumor-associated myeloid cells (TAMCs). Inhibiting the myeloid compartment using intracranial anti-Gr1 antibody in combination with PD1 blockade resulted in B-cells exhibiting greater proliferation and differentiation into memory B-cells in addition to germinal-center-like B-cells. Further demonstrating B-cell functional reprogramming, autologous T cells isolated from spleens exhibited greater proliferation and robust anti-tumor cytotoxicity when cocultured with tumor-associated B-cells from the dual treatment group. Finally, inhibiting a5b8 integrin, a key complex in releasing active TGFb, increased tumor-infiltrating proliferating B-cells and conferred a long-term survival benefit in the CT2A murine model. Our results demonstrate that the immunosuppressive TME of GBM is influenced by the vital interplay between B-cells and the TME through TGFb signaling. This study highlights the potential therapeutic benefits of targeting the TGFb signaling pathway in conjunction with the current standard of care for GBM.

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A phase II study of niraparib in combination with EGFR inhibitor panitumumab in patients with advanced colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.tps269 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. TPS269-TPS269

Author(s):

Olatunji B. Alese ◽

Walid Labib Shaib ◽

Mehmet Akce ◽

Christina Wu ◽

Gregory B. Lesinski ◽

...

Keyword(s):

Dna Repair ◽

Synthetic Lethality ◽

Resistance Mechanism ◽

Growth Factor Receptor ◽

Standard Of Care ◽

Ki 67 ◽

Egfr Inhibition ◽

Platinum Sensitivity ◽

Anticancer Properties ◽

Biomarker Analysis

TPS269 Background: Panitumumab (Pmab) is a recombinant monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR), and is indicated for metastatic colorectal carcinoma (mCRC). EGFR inhibition induces synthetic lethality with poly ADP ribose polymerase inhibitors (PARPi) by attenuating DNA repair pathways. This susceptibility to PARPi-induced cell death by EGFR inhibition is associated with deficient Non-homologous end joining (NHEJ), and Homologous recombination (HR) mediated DNA repair and persistence of DNA damage. Furthermore, efficacy of PARPi (such as niraparib) is highly correlated with platinum sensitivity. Cancer cell sensitivity and resistance to both PARPi and platinum have been associated with loss and restoration of HR DNA repair, indicating similar mechanisms of anticancer activity and resistance. Platinum sensitivity in CRC could therefore predict for anticancer properties of PARPi when utilized in the setting of synthetic lethality. Combining PARP and EGFR inhibition has the potential to confer synergistic benefit, while ameliorating resistance mechanism to PARPi. This study aims to evaluate the activity of the combination of niraparib and Pmab in RAS wildtype (WT) mCRC. Methods: Eligible patients for the trial include advanced, RAS WT mCRC who have been intolerant of, progressed on, or failed at least one line of systemic chemotherapy. Those currently on first line oxaliplatin-containing regimen are allowed on the trial if they have remained stable or better (PR or CR) for at least 4 months on that line of treatment, and are being considered for maintenance therapy as standard of care. Patients must also be 18 years old, ECOG PS 0-1 and measurable disease per RECIST 1.1. A safety run-in cohort of 6 eligible patients, and additional 20 patients with the same inclusion criteria will be enrolled. Pmab dose - 6 mg/kg IV on days 1 & 15 of each 28-day cycle; Niraparib - 200mg or 300mg (based on body weight and platelet count) orally continuously. Primary endpoint: clinical benefit rate (CR +PR + SD). Biomarker analysis includes skin biopsies evaluated for p-Caspace-3, PARP, p-MAPK, Ki-67, and p27. The study was activated in Sept. 2019. Clinical trial information: NCT03983993.

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Patient Indications for Mohs Micrographic Surgery: A Systematic Review

Journal of Cutaneous Medicine and Surgery ◽

10.1177/1203475418786208 ◽

2018 ◽

Vol 23 (1) ◽

pp. 75-90 ◽

Cited By ~ 1

Author(s):

Christian Murray ◽

Duvaraga Sivajohanathan ◽

Timothy P. Hanna ◽

Scott Bradshaw ◽

Nowell Solish ◽

...

Keyword(s):

Skin Cancer ◽

Retrospective Studies ◽

Standard Of Care ◽

Mohs Micrographic Surgery ◽

Micrographic Surgery ◽

Skin Cancers ◽

Cochrane Database ◽

The Face ◽

Aggressive Histology

The purpose of the present review was to describe evidence-based indications for Mohs micrographic surgery (MMS) in patients with a diagnosis of skin cancer. Relevant studies were identified from a systematic MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews search of studies published from 1970 to 2017. Randomized controlled trials (RCTs), prospective and retrospective comparative studies with greater than 30 patients, and single-arm retrospective studies with multivariate analyses were included. A total of 2 RCTs, 3 prospective studies, and 16 retrospective studies (14 comparative and 2 single-arm) were included. Data on recurrence rate, cure rate, complications, cosmesis, and quality of life were extracted. Surgery (with postoperative or intraoperative marginal assessment) or radiation for those who are ineligible for surgery should remain the standard of care for patients with skin cancer given the lack of high-quality, comparative evidence. MMS is recommended for those with histologically confirmed recurrent basal cell carcinoma (BCC) of the face and is appropriate for primary BCCs of the face that are >1 cm, have aggressive histology, or are located on the H zone of the face. The available evidence is difficult to generalize to all patients with skin cancer because the evidence did not adequately cover non-BCC skin cancers; however, those skin cancers can be considered on a case-by-case basis for MMS. MMS should be performed by physicians who have completed a degree in medicine or equivalent, including a Royal College of Physicians and Surgeons of Canada Specialist Certificate or equivalent, and have received advanced training in MMS.

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Tyrosyl-DNA Phosphodiesterase 1 and Topoisomerase I Activities as Predictive Indicators for Glioblastoma Susceptibility to Genotoxic Agents

Cancers ◽

10.3390/cancers11101416 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1416 ◽

Cited By ~ 1

Author(s):

Wenjie Wang ◽

Monica Rodriguez-Silva ◽

Arlet M. Acanda de la Rocha ◽

Aizik L. Wolf ◽

Yanhao Lai ◽

...

Keyword(s):

Topoisomerase I ◽

Activity Ratio ◽

Pearson Correlation ◽

Ectopic Expression ◽

Standard Of Care ◽

Patient Responsiveness ◽

Ic50 Values ◽

Cleavage Complex ◽

Predictive Indicator ◽

Selection Of

Glioblastoma (GBM) patients have an estimated survival of ~15 months with treatment, and the standard of care only modestly enhances patient survival. Identifying biomarkers representing vulnerabilities may allow for the selection of efficacious chemotherapy options to address personalized variations in GBM tumors. Irinotecan targets topoisomerase I (TOP1) by forming a ternary DNA–TOP1 cleavage complex (TOP1cc), inducing apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair enzyme that may reduce the effectiveness of irinotecan. We treated GBM cell lines with increasing concentrations of irinotecan and compared the IC50 values. We found that the TDP1/TOP1 activity ratio had the strongest correlation (Pearson correlation coefficient R = 0.972, based on the average from three sets of experiments) with IC50 values following irinotecan treatment. Increasing the TDP1/TOP1 activity ratio by the ectopic expression of wild-type TDP1 increased in irinotecan IC50, while the expression of the TDP1 catalytic-null mutant did not alter the susceptibility to irinotecan. The TDP1/TOP1 activity ratio may be a new predictive indicator for GBM vulnerability to irinotecan, allowing for the selection of individual patients for irinotecan treatment based on risk–benefit. Moreover, TDP1 inhibitors may be a novel combination treatment with irinotecan to improve GBM patient responsiveness to genotoxic chemotherapies.

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T cell–induced CSF1 promotes melanoma resistance to PD1 blockade

Science Translational Medicine ◽

10.1126/scitranslmed.aan3311 ◽

2018 ◽

Vol 10 (436) ◽

pp. eaan3311 ◽

Cited By ~ 81

Author(s):

Natalie J. Neubert ◽

Martina Schmittnaegel ◽

Natacha Bordry ◽

Sina Nassiri ◽

Noémie Wald ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Resistance Mechanism ◽

Immune Checkpoint Blockade ◽

Human Melanoma ◽

Checkpoint Blockade ◽

Data Sets ◽

Adaptive Resistance ◽

Pd1 Blockade

Colony-stimulating factor 1 (CSF1) is a key regulator of monocyte/macrophage differentiation that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). We show that CSF1 is expressed in human melanoma, and patients with metastatic melanoma have increased CSF1 in blood compared to healthy subjects. In tumors, CSF1 expression correlated with the abundance of CD8+T cells and CD163+TAMs. Human melanoma cell lines consistently produced CSF1 after exposure to melanoma-specific CD8+T cells or T cell–derived cytokines in vitro, reflecting a broadly conserved mechanism of CSF1 induction by activated CD8+T cells. Mining of publicly available transcriptomic data sets suggested co-enrichment of CD8+T cells with CSF1 or various TAM-specific markers in human melanoma, which was associated with nonresponsiveness to programmed cell death protein 1 (PD1) checkpoint blockade in a smaller patient cohort. Combination of anti-PD1 and anti–CSF1 receptor (CSF1R) antibodies induced the regression ofBRAFV600E-driven, transplant mouse melanomas, a result that was dependent on the effective elimination of TAMs. Collectively, these data implicate CSF1 induction as a CD8+T cell–dependent adaptive resistance mechanism and show that simultaneous CSF1R targeting may be beneficial in melanomas refractory to immune checkpoint blockade and, possibly, other T cell–based therapies.

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Age-related factors in cyclosporine-induced syngeneic graft-versus-host disease: regulatory role of marrow-derived T lymphocytes.

Journal of Experimental Medicine ◽

10.1084/jem.172.1.85 ◽

1990 ◽

Vol 172 (1) ◽

pp. 85-94 ◽

Cited By ~ 20

Author(s):

A C Fischer ◽

A D Hess

Keyword(s):

T Lymphocytes ◽

Graft Versus Host Disease ◽

Host Resistance ◽

Resistance Mechanism ◽

Inverse Correlation ◽

Regulatory Effect ◽

Related Factors ◽

Host Disease ◽

Graft Versus Host ◽

Age Related

The present studies have evaluated the effect of age on the induction of syngeneic graft-versus-host disease (SGVHD) after syngeneic bone marrow transplantation (BMT) and cyclosporine (CsA) therapy. The results clearly document an inverse correlation of age with the incidence of SGVHD. Virtually a 100% incidence of SGVHD occurs in Lewis rats when syngeneic BMT and CsA therapy are started when the animals are 4 wk of age. Thereafter, there is a dramatic decline in the incidence of SGVHD with the increasing age of the animals. Although the age of the recipient was important, the most significant effect was the age of the marrow donor. Marrow from animals 6 mo of age was virtually incapable of eliciting SGVHD after BMT and CsA therapy. Furthermore, mixing the marrow from mature and immature animals resulted in a decreased incidence of SGVHD, implicating a regulatory effect present in the marrow from older rats. This regulatory effect was due to the presence of mature T cells in the marrow from animals 6 mo of age. Despite the fact that marrow from young animals possesses mature T lymphocytes, this regulatory activity was absent, suggesting that the host resistance mediated by T lymphocytes develops as the animal ages. These data further implicate the importance of a host resistance mechanism in preventing the induction of SGVHD with CsA, which appears to be mediated by the clonal inactivation of autoreactive cells.

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A phase 1 first-in-human study of the anti-LAG-3 antibody MK4280 (favezelimab) plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3584 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3584-3584

Author(s):

Elena Garralda ◽

Ammar Sukari ◽

Nehal J. Lakhani ◽

Amita Patnaik ◽

Yanyan Lou ◽

...

Keyword(s):

Colorectal Cancer ◽

Phase 1 ◽

Treatment Options ◽

Human Study ◽

Lymphocyte Activation ◽

Standard Of Care ◽

Analysis Data ◽

Treatment Naïve ◽

Full Analysis ◽

Grade 3

3584 Background: Patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed on ≥2 prior therapies have limited treatment options, with median OS ranging from 6-9 months (mo). In the dose-escalation phase of this first-in-human multicohort study (NCT02720068), the anti-lymphocyte activation gene (LAG)-3 antibody favezelimab (fave) was well tolerated alone and with pembrolizumab (pembro) across all dose levels (Lakhani, SITC, 2018, abstract O26). Here, we evaluate the safety and efficacy of fave alone or in combination with pembro in pts with advanced MSS CRC from the dose confirmation phase. Methods: Eligible pts with MSS PD-1/PD-L1-treatment-naïve mCRC that progressed on prior standard-of-care (3L+) were enrolled (cohort A) to receive the RP2D of 800 mg fave alone (Arm 1), 800 mg fave + 200 mg pembro (Arm 2C), or 800 mg fave + 200 mg pembro (MK-4280A) co-formulation (Arm 5), all Q3W. Treatment continued for 35 cycles or until progression, unacceptable toxicity, or investigator/pt decision. Pts with confirmed progression per irRECIST v1.1 on fave alone could crossover to 800 mg fave + pembro. Safety was assessed in all treated pts; efficacy in the full analysis set (FAS) of all treated pts with baseline scan. Objectives included safety (primary), ORR (RECIST v1.1 by investigator [secondary]), and DOR, PFS, and OS (exploratory). Interim analysis data cut-off was: Oct. 23, 2020. Results: A total of 20 pts received fave (Arm 1); 89 pts (including 9 crossover) received fave + pembro (Arms 2C+5); 12 pts (Arm 1) and 36 pts (Arms 2C+5), had PD-L1 CPS ≥1 tumors. At data cut-off, median follow-up was 5.8 months (mo) in Arm 1 and 6.2 mo in Arms 2C+5. Treatment-related adverse events (TRAEs) were 65% with fave (Arm 1) and 65.2% with fave + pembro (Arms 2C+5). Grade ≥3 TRAEs were 15% (Arm 1), and 20% [Arms 2C+5]). No grade 5 TRAEs were reported. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15%) with fave, and fatigue (16.9%) with fave + pembro. Confirmed ORR was 6.3% (4PR, 1CR) with fave + pembro (Arms 2C+5). No pt receiving fave alone responded. In Arms 2C+5, median DOR was 10.6 mo (range, 5.6-12.7). ORR, OS and PFS by PD-L1 status are reported in the Table. Conclusions: Favezelimab alone or in combination with pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, including with MK-4280A, compared with monotherapy most notably in pts with PD-L1 CPS ≥1 tumors. Clinical trial information: NCT02720068. [Table: see text]

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