anti-PD1 Immune Checkpoint Inhibitor Research Articles

Neoadjuvant followed by adjuvant pembrolizumab in melanoma: time biases in the data analysis of the SWOG S1801 trial.

The SWOG S1801 trial investigated the role of pembrolizumab, an anti-PD1 immune checkpoint inhibitor, in the perioperative setting of stage III or IV melanoma. This phase 2 trial compared two groups: one receiving pembrolizumab both before and after surgery (neoadjuvant-adjuvant), and another receiving it only post-surgery (adjuvant-only), with event-free survival (EFS) as the primary endpoint. Neoadjuvant strategies, involving pre-surgical drug administration, potentially offer rapid tumor control and a unique opportunity to assess tumor response. However, they may expose to toxicity and delay or preclude surgery. The study met its primary endpoint, with a 72 % EFS rate in the neoadjuvant-adjuvant group, and 49 % in the adjuvant group. Here, we question the results' applicability with three potential limitations. Key concerns include an arbitrary rule in event assignment, possibly affecting the event distribution over time. Second, different rates of early censoring between groups introduce the possibility of informative censoring, which could have led to an artefactual benefit in EFS. Lastly, phase 2 trial results, by definition, carry risk of fluke results, and should be confirmed in phase 3 trial before wide adoption. Collectively, these factors must be integrated into a careful interpretation of the SWOG S1801 trial outcomes. More robust data are needed to fully appraise strengths and limitations of neoadjuvant pembrolizumab in melanoma treatment.

Abstract 2609: Vesicular LGALS3BP is a neuroblastoma biomarker and a therapeutic target for combination therapy with antibody-drug conjugate and checkpoint inhibitors

Abstract We have recently shown that targeting circulating LGALS3BP with a maytansinoid-based non-internalizing antibody-drug conjugate (ADC) resulted in tumor eradication of high-risk NMYC-amplified neuroblastoma patient-derived xenografts. LGALS3BP is a high molecular weight, hyperglycosylated and secreted protein which is enriched at the surface of cancer-derived extracellular vesicles (EVs). Here, using a neuroblastoma pseudometastatic preclinical model, we extended our previous work demonstrating that EVs-associated LGALS3BP strictly correlates with disease progression and dissemination. Moreover, to investigate whether LGALS3BP ADC, named 1959sss/DM4, possesses immune-modulating properties, we analyzed DM4 ability to induce immunogenic cell death (ICD). Interestingly, using NXS2 murine neuroblastoma cells, we found that DM4 induced a time-dependent surface expression of three different ICD marker, i.e. calreticulin, HSP70 and HSP90. As it was recently demonstrated that to limit immune surveillance NXS2 cells increase PD-L1 expression in response to IFNγ production in the tumor immune infiltrate, we evaluated potential synergism between LGALS3BP targeting ADC and an anti-PD1 immune check-point inhibitor. To this aim, we genetically manipulated NXS2 cells which resulted nearly negative for murine LGALS3BP expression. Therefore, using a lentivirus-based gene transduction system, we obtained NXS2 cells producing large amounts of vesicular human LGALS3BP. Of note, the vesicular LGALS3BP could be quantified by ELISA and imaged by confocal microscopy using 1959 antibody. Strikingly, while single agent treatment showed a limited antitumor activity in NXS2-LGALS3BP syngeneic model, the LGALS3BP ADC/anti-PD1 combination resulted in a marked inhibition of tumor growth, which was followed by a prolonged survival. In conclusion, our findings establish that vesicular LGALS3BP is a potential biomarker for liquid biopsy and reveals this protein as a suitable target for therapeutic strategy that combines 1959sss/DM4 ADC with immune checkpoint blockade for the treatment of LGALS3BP expressing neuroblastoma. Citation Format: Gianluca Sala, Emily Capone, Ilaria Cela, Giulio Lovato, Alessia Lamolinara, Manuela Iezzi, Cosmo Rossi, Vincenzo De Laurenzi, Rodolfo Ippoliti, Stefano Iacobelli. Vesicular LGALS3BP is a neuroblastoma biomarker and a therapeutic target for combination therapy with antibody-drug conjugate and checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2609.

Abstract 1167: Prospective analysis of pretreatment circulating CD4 memory T cell features associated with severe immunotherapy toxicity

Abstract Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, significantly improving outcomes. Nevertheless, too many melanoma patients undergoing ICI treatment experience severe and often debilitating immune-related adverse events (irAEs). In a retrospective melanoma cohort treated with ICIs, we previously found that elevated baseline levels of circulating CD4 effector memory T (TEM) cells were associated with the development of severe irAEs, irrespective of the affected organ system (Lozano et al., Nature Medicine, 2022). Here, we present data from an extended prospective validation cohort from 47 patients across two academic medical centers. Methods: Of 47 patients, 26 received combination anti-PD1/anti-CTLA4 ICIs, 3 combination anti-PD1/anti-LAG3 ICIs, 17 anti-PD1 ICI, and 1 anti-CTLA4 ICI. Peripheral blood mononuclear cells (PBMCs) were prepared from pretreatment (Cycle 1 Day 1) blood samples obtained from all patients. We performed mass cytometry (CyTOF) on PBMCs using a 38-marker panel to deeply profile immune subsets. We further leveraged bulk RNA-seq from 24 patients to (i) deconvolve CD4 memory T cell abundance using CIBERSORTx and (ii) determine T cell receptor (TCR) diversity using Shannon entropy following MiXCR clonotype assembly. irAEs were graded on a 5-point scale using the Common Terminology Criteria for Adverse Events v5. Results: After treatment initiation, 14 patients experienced severe irAEs (grade 3+) at a median of 12.1 weeks (range 4-54), including 4 with life-threatening (grade 4) irAEs. CyTOF revealed elevated circulating CD4 TEM cells in patients that developed severe irAEs (P<0.0001; AUC=0.87), including those treated with combination ICIs (P=0.0001; AUC=0.89). We further observed a continuous relationship between increasing CD4 TEM levels and irAE grade (P=3e-6, Jonckheere-Terpstra test). We then combined CD4 memory T cell abundance and TCR diversity derived from bulk RNA-seq on 24 of these patients using logistic regression (trained on data from Lozano et al.) to yield a composite model score. The pretreatment composite model score was strongly associated with severe irAE development (P=0.0009, AUC=0.88), and in a median split, identified patients with shorter time to severe irAE development (3 months vs. not reached; P=0.006; HR=10.5). Notably, composite model features and the overall score had no significant association with immunotherapy benefit. Conclusion: In this prospective study, both circulating CD4 TEM levels determined by CyTOF and a composite model score measured by RNA-seq were strongly associated with severe irAE development, independent of response status. These findings hold promise for future pretreatment risk stratification of ICI therapy. Citation Format: Abul Usmani, Noah Earland, Wubing Zhang, Peter K. Harris, Antonietta Bacchiocchi, Chloe M. Sachs, Aishwarya Nene, David Y. Chen, Mario Sznol, Ruth Halaban, Aaron M. Newman, Aadel A. Chaudhuri. Prospective analysis of pretreatment circulating CD4 memory T cell features associated with severe immunotherapy toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1167.

HLA-DR expression in melanoma: from misleading therapeutic target to potential immunotherapy biomarker.

Since the advent of anti-PD1 immune checkpoint inhibitor (ICI) immunotherapy, cutaneous melanoma has undergone a true revolution with prolonged survival, as available 5-year updates for progression-free survival and overall survival demonstrate a durable clinical benefit for melanoma patients receiving ICI. However, almost half of patients fail to respond to treatment, or relapse sooner or later after the initial response to therapy. Little is known about the reasons for these failures. The identification of biomarkers seems necessary to better understand this resistance. Among these biomarkers, HLA-DR, a component of MHC II and abnormally expressed in certain tumor types including melanoma for unknown reasons, seems to be an interesting marker. The aim of this review, prepared by an interdisciplinary group of experts, is to take stock of the current literature on the potential interest of HLA-DR expression in melanoma as a predictive biomarker of ICI outcome.

Abstract A018: Characterization of macrophage population in head and neck squamous cell carcinoma and renal cell carcinoma and their role in modulating immune checkpoint blockade response

Abstract Tumor-associated macrophages (TAMs) and monocytes are an integral part of tumor microenvironment (TME) which modulates disease progression. M1 and M2 are the two well-defined subtypes of TAMs whose polarization influence response to immune checkpoint inhibitors (ICIs). Unavailability of data from complex models poses limitations to extensive characterization of these immune subpopulations. In this study, we have evaluated the role of monocytes and TAMs in modulating response to ICI, using the FarcastTM TruTumor histoculture platform. Two different cancer indications, Head and Neck Squamous Cell Carcinoma (HNSCC) and Renal Cell Carcinoma (RCC) were used in the study. HNSCC (n = 25) and RCC (n = 24) tissue samples were collected along with matched blood from the consented patients, post-surgery. Tissue explants were generated and allotted to arms and cultured for 72 hours. Fifteen samples from both indication were treated with anti-PD1 ICI, Nivolumab at a concentration of 132 µg/ml. Macrophage and monocyte sub-populations were characterized by performing flow cytometry, and cytokine (tumor necrosis factor-α (TNF-α), and interferon gamma (IFN-γ)) analysis. In HNSCC, a higher proportion of monocytes compared to RCC (p = 0.02) was observed. Though total TAM proportions in the two indications exhibited no significant difference, a significantly higher proportion of M1/M2 was observed in RCC (p = 0.006) as compared to HNSCC. In addition, RCC also exhibited higher secretion of TNF-α (p = 0.08) as compared to HNSCC. Eleven out of fifteen HNSCC samples (73%) exhibited more than 1.2-fold increase in IFN-γ secretion as opposed to only 6/13 RCC samples (46%), on treatment with Nivolumab. However, the correlation between fold change, with respect to control, in IFN- γ secretion and tumor content was much stronger in RCC (ρ=-0.82; p=0.0009) as compared to HNSCC (ρ=-0.07; p=0.81). This observation could be explained by a comparatively higher immunosuppressive microenvironment in HNSCC, potentially mediated by a higher monocyte subpopulation. On the other hand, the relatively higher M1/M2 ratio in RCC seemed to potentially enhance Nivolumab treatment efficacy as compared to HNSCC. Spatial orientation of macrophage sub-population could give further insights into the role they play in TME. Thus, FarcastTM TruTumor is a relevant platform to characterize the monocyte and TAM population in TME across different cancer indications and to investigate their role in modulating ICI response. Citation Format: Moumita Nath, Nandini Pal Basak, Kowshik Jaganathan, Oliyarasi M, Rajashekar M, Saurabh Bhargava, Amritha Suresh, Lalitha Laxhmi, Jayaprakash Chandra Reddy, Ganesh Mandakulutur Subramanya, Amritha Prabha, Prakash BV, Biswajit Das, Syamkumar V, Chandan Bhowal, Mouniss M, Dharanidharan M, Ritu Malhotra, Govindraj K, Mohit Malhotra, Satish Sankaran. Characterization of macrophage population in head and neck squamous cell carcinoma and renal cell carcinoma and their role in modulating immune checkpoint blockade response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A018.

Fungal Depletion Bolsters Anti-Tumor Immune Response Elicited by Anti-PD1 Alone and in Combination with Radiation Therapy

Pembrolizumab in combination with chemotherapy has become the standard of care treatment for both metastatic and early-stage triple negative breast cancer (TNBC). Clinical trials are currently underway investigating the use of pembrolizumab with radiation in the neoadjuvant setting in early TNBC. Several groups have described a link between the microbiome and the efficacy of chemotherapy and anti-PD1 immune checkpoint inhibitors (ICIs) in preclinical models. Recent work from our lab has shown that targeting commensal fungi in the microbiome enhances the radiation induced antitumor immune response. Therefore, we hypothesized that fungal depletion might positively impact anti-PD1 therapy and combination treatment with anti-PD1 and radiation therapy (RT). This study utilized an orthotopic syngeneic breast tumor model in which the syngeneic cell line E0771 was injected into the mammary fat pad of female C57BL/6 mice. Tumor-bearing mice were then treated with and without the antifungal fluconazole, anti-PD1, and radiation (16 Gy single fraction) using the X-RAD SmART platform with CT guidance. Tumor volumes were compared using 2-way ANOVA and survival curves analyzed using log rank. In a separate set of experiments, tumor-infiltrating immune cells were isolated and analyzed by high-dimensional multiplex flow cytometry. We found that fungal depletion with fluconazole prior to treatment with anti-PD1 reduced the tumor volume and significantly improved survival in comparison to those treated with anti-PD1 alone (P = 0.0016). To identify what changes in the tumor immune microenvironment is driving this increased anti-tumor response, we performed flow cytometry on immune cells isolated from the tumors. We found that the use of fluconazole prior to anti-PD1 treatment reduced the proportion of CD11b+F4/80+ tumor-associated macrophages (TAMs) (P = 0.01) and increased tumor infiltrating cytotoxic T cell population (P = 0.04) when compared with the use of anti-PD1 alone. We also evaluated the effect of fungal depletion on combination therapy with RT and anti-PD1. Strikingly, we found that mice depleted of fungi with fluconazole prior to radiation and anti-PD1 therapy, have decreased tumor burden and significantly increased survival when compared to their fungally-intact counterparts (P = 0.043). Our data indicates that the depletion of the gut fungal populations induces an increased antitumor response following anti-PD1 alone and in combination with radiation. This increased antitumor immune response is associated with an increase in the cytotoxic CD8+ T cell compartment with concomitant decrease in immunosuppressive tumor associated macrophages.

Modern Approach to Melanoma Adjuvant Treatment with Anti-PD1 Immune Check Point Inhibitors or BRAF/MEK Targeted Therapy: Multicenter Real-World Report.

The landscape of melanoma management changed as randomized trials have launched adjuvant treatment. An analysis of data on 248 consecutive melanoma stage III and IV patients given adjuvant therapy in eight centers (February 2019 to January 2021) was conducted. The analyzed cohort comprised 147 melanoma patients given anti-PD1 (33% nivolumab, 26% pembrolizumab), and 101 (41%) were given dabrafenib plus trametinib (DT). The 2-year overall survival (OS), relapse-free survival (RFS), and distant-metastases-free survival (DMFS) rates were 86.7%, 61.4%, and 70.2%, respectively. The disease stage affected only the RFS rate; for stage IV, it was 52.2% (95% CI: 33.4-81.5%) vs. 62.5% (95% CI: 52.3-74.8%) for IIIA-D, p = 0.0033. The type of lymph node surgery before adjuvant therapy did not influence the outcomes. Completion of lymph node dissection cessation after positive SLNB did not affect the results in terms of RFS or OS. Treatment-related adverse events (TRAE) were associated with longer 24-month RFS, with a rate of 68.7% (55.5-84.9%) for TRAE vs. 56.6% (45.8-70%) without TRAE, p = 0.0031. For TRAE of grade ≥ 3, a significant decline in OS to 60.6% (26.9-100%; p = 0.004) was observed. Melanoma adjuvant therapy with anti-PD1 or DT outside clinical trials appears to be effective and comparable with the results of registration studies. Our data support a de-escalating surgery approach in melanoma treatment.

Phase 2 trial of epidermal growth factor (EGF) vaccine CIMAvax in combination with pembrolizumab in first line and maintenance setting in advanced non–small cell lung cancer patients.

TPS2677 Background: CIMAvax-EGF is a novel growth-factor depleting immunotherapy consisting of human recombinant EGF conjugated to recombinant P64k derived from Neisseria meningitidis, that elicits an anti-EGF antibody response, resulting in reduction of circulating EGF levels. A randomized phase 3 study of CIMAvax-EGF administered as switch maintenance therapy after first-line platinum-based chemotherapy in patients with advanced NSCLC demonstrated overall survival (OS) advantage in comparison to best supportive care alone, particularly in patients with high baseline serum EGF levels. A phase 1 trial combining CIMAvax-EGF with nivolumab, an anti-PD1 immune checkpoint inhibitor, showed that the combination is safe and appears to induce higher rate of good anti-EGF antibody response within the first 8 weeks of therapy compared to historical comparison group receiving CIMAvax-EGF alone. CIMAvax-EGF is currently being investigated in combination with pembrolizumab in a multi-arm phase II trial as 1L therapy in combination with pembrolizumab for patients with EGFR/ALK wildtype NSCLC and PD-L1 > 50% (Cohort C) and as maintenance therapy after completing 1L chemoimmunotherapy for patients with PD-L1 < 50% (Cohorts D and E). Accrual to this trial is ongoing (NCT02955290). Methods: This is an open-label, non-randomized, multi-site, phase 2 basket trial. CIMAvax-EGF (2.4 mg IM every 2 weeks x 4 doses, then every 4 weeks thereafter) is being tested as first-line therapy in combination with pembrolizumab (200 mg IV every 4 weeks) in patients with advanced NSCLC with PD-L1 ≥ 50% (Cohort C), using a Simon two stage design (n up to 41). A safety lead-in consisting of the first 6 NSCLC patients was completed. There were no G3 or higher adverse events attributed to the combination within the first 4 weeks of protocol treatment. Patients with advanced squamous NSCLC (Cohort D, n=50) and non-squamous NSCLC (without EGFR/ALK/ROS-1/KRAS mutations; Cohort E, n=45) with PD-L1 expression <50% and no evidence of progression of disease by RECIST 1.1 criteria after at least 4 cycles of induction platinum-based doublet with pembrolizumab, prior to initiation of standard of care maintenance therapy will be enrolled to receive protocol treatment with pembrolizumab in combination with CIMAvax-EGF as maintenance therapy. The primary endpoint is to evaluate objective response rate (Cohort C), and 12-month PFS in Cohorts D and E. Secondary endpoints include 12-month overall survival in all cohorts. Exploratory objectives include characterizing tissue-based immune and EGFR signaling profile as well as serum EGF levels, anti-EGF antibody levels and other blood-based biomarkers in relation to clinical outcomes. Clinical trial information: NCT02955290 .

Non-small cell lung cancer patients treated with Anti-PD1 immunotherapy show distinct microbial signatures and metabolic pathways according to progression-free survival and PD-L1 status

ABSTRACT Due to the high variance in response rates concerning anti-PD1 immunotherapy (IT), there is an unmet need to discover innovative biomarkers to predict immune checkpoint inhibitor (ICI)-efficacy. Our study included 62 Caucasian advanced-stage non-small cell lung cancer (NSCLC) patients treated with anti-PD1 ICI. Gut bacterial signatures were evaluated by metagenomic sequencing and correlated with progression-free survival (PFS), PD-L1 expression and other clinicopathological parameters. We confirmed the predictive role of PFS-related key bacteria with multivariate statistical models (Lasso- and Cox-regression) and validated on an additional patient cohort (n = 60). We find that alpha-diversity showed no significant difference in any comparison. However, there was a significant difference in beta-diversity between patients with long- (>6 months) vs. short (≤6 months) PFS and between chemotherapy (CHT)-treated vs. CHT-naive cases. Short PFS was associated with increased abundance of Firmicutes (F) and Actinobacteria phyla, whereas elevated abundance of Euryarchaeota was specific for low PD-L1 expression. F/Bacteroides (F/B) ratio was significantly increased in patients with short PFS. Multivariate analysis revealed an association between Alistipes shahii, Alistipes finegoldii, Barnesiella visceriola, and long PFS. In contrast, Streptococcus salivarius, Streptococcus vestibularis, and Bifidobacterium breve were associated with short PFS. Using Random Forest machine learning approach, we find that taxonomic profiles performed superiorly in predicting PFS (AUC = 0.74), while metabolic pathways including Amino Acid Synthesis and Fermentation were better predictors of PD-L1 expression (AUC = 0.87). We conclude that specific metagenomic features of the gut microbiome, including bacterial taxonomy and metabolic pathways might be suggestive of ICI efficacy and PD-L1 expression in NSCLC patients.

Rheumatic Diseases Development in Patients Treated by Anti-PD1 Immune Checkpoint Inhibitors: A Single-Centre Descriptive Study.

The introduction of the so-called immune checkpoint inhibitors (ICIs) substantially changed the history of cancer therapy. On the other hand, they can induce the development of rheumatic immune-related adverse events (Rh-irAEs). In the scenario of a joint oncology/rheumatology outpatient clinic, we conducted a single-centre descriptive study to define from a laboratory, clinical and therapeutic point of view, rheumatic conditions developed during anti-PD1 treatment. The study included 32 patients (M/F 16/16, median age 69, IQR 16.5). According to the international classification criteria, eight patients could be classified as affected by Rheumatoid Arthritis, one by Psoriatic Arthritis, six by Polymyalgia Rheumatica, five by systemic connective tissue diseases (two systemic lupus erythematosus, two Sjögren's syndrome, one undifferentiated connective tissue disease). The remaining patients were diagnosed as having undifferentiated arthritis or inflammatory arthralgia. The median interval between ICIs starting and the onset of symptoms was 14 weeks (IQR 19.75). Moving to treatment, the longitudinal observation revealed that all RA, PsA and CTD patients required the introduction of treatment with DMARDs. In conclusion, the growing use of ICIs in a real-life setting confirmed the possible development of different rheumatological conditions, further emphasising the need for shared oncology/rheumatology management.

SOLTI-1904 ACROPOLI TRIAL: efficacy of spartalizumab monotherapy across tumor-types expressing high levels of PD1 mRNA.

Improved selection of cancer patients who are most likely to respond to immune checkpoint inhibitors remains an unmet clinical need. Recently, a positive correlation between levels of PD1 mRNA and clinical outcome in response to PD1 blockade across diverse tumor histologies has been confirmed in several datasets. ACROPOLI is a parallel cohort, non-randomized, phase II study that aims to evaluate the efficacy of the anti-PD1 immune checkpoint inhibitor spartalizumab as monotherapy in metastatic patients with solid tumors that express high levels of PD1 (cohort 1; n=111). An additional cohort of 30 patients with tumors expressing low levels of PD1, where PD1/PD-L1 antibodies in monotherapy are standard treatment, will also be included (cohort 2). Primary end point is overall response rate in cohort 1. Trial registration number: NCT04802876 (ClinicalTrials.gov).

Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures.

Melanoma is a highly aggressive skin cancer, which, although highly immunogenic, frequently escapes the body’s immune defences. Immune checkpoint inhibitors (ICI), such as anti-PD1, anti-PDL1, and anti-CTLA4 antibodies lead to reactivation of immune pathways, promoting rejection of melanoma. However, the benefits of ICI therapy remain limited to a relatively small proportion of patients who do not exhibit ICI resistance. Moreover, the precise mechanisms underlying innate and acquired ICI resistance remain unclear. Here, we have investigated differences in melanoma tissues in responder and non-responder patients to anti-PD1 therapy in terms of tumour and immune cell gene-associated signatures. We performed multi-omics investigations on melanoma tumour tissues, which were collected from patients before starting treatment with anti-PD1 immune checkpoint inhibitors. Patients were subsequently categorized into responders and non-responders to anti-PD1 therapy based on RECIST criteria. Multi-omics analyses included RNA-Seq and NanoString analysis. From RNA-Seq data we carried out HLA phenotyping as well as gene enrichment analysis, pathway enrichment analysis and immune cell deconvolution studies. Consistent with previous studies, our data showed that responders to anti-PD1 therapy had higher immune scores (median immune score for responders = 0.1335, median immune score for non-responders = 0.05426, p-value = 0.01, Mann-Whitney U two-tailed exact test) compared to the non-responders. Responder melanomas were more highly enriched with a combination of CD8+ T cells, dendritic cells (p-value = 0.03) and an M1 subtype of macrophages (p-value = 0.001). In addition, melanomas from responder patients exhibited a more differentiated gene expression pattern, with high proliferative- and low invasive-associated gene expression signatures, whereas tumours from non-responders exhibited high invasive- and frequently neural crest-like cell type gene expression signatures. Our findings suggest that non-responder melanomas to anti-PD1 therapy exhibit a de-differentiated gene expression signature, associated with poorer immune cell infiltration, which establishes a gene expression pattern characteristic of innate resistance to anti-PD1 therapy. Improved understanding of tumour-intrinsic gene expression patterns associated with response to anti-PD1 therapy will help to identify predictive biomarkers of ICI response and may help to identify new targets for anticancer treatment, especially with a capacity to function as adjuvants to improve ICI outcomes.

The Effects of 6 Common Antidiabetic Drugs on Anti-PD1 Immune Checkpoint Inhibitor in Tumor Treatment

Diabetes and cancer are common diseases and are frequently diagnosed in the same individual. These patients need to take antidiabetic drugs while receiving antitumor drugs therapy. Recently, immunotherapy offers significant advances for cancer treatment. However, it is unclear whether antidiabetic drugs affect immunotherapy. Here, by employing syngeneic mouse colon cancer model and melanoma model, we studied the effects of 6 common antidiabetic drugs on anti-PD1 immune checkpoint inhibitor in tumor treatment, including acarbose, sitagliptin, metformin, glimepiride, pioglitazone, and insulin. We found that acarbose and sitagliptin enhanced the tumor inhibition of anti-PD1, and metformin had no effect on the tumor inhibition of anti-PD1, whereas glimepiride, pioglitazone, and insulin weakened the tumor inhibition of anti-PD1. Our study suggests that cancer patients receiving anti-PD1 antibody therapy need serious consideration when choosing antidiabetic drugs. In particular, acarbose significantly inhibited tumor growth and further enhanced the therapeutic effect of anti-PD1, which can be widely used in tumor therapy. Based on this study, further clinical trials are expected.

A phase 1b study (STELLAR-002) of XL092 administered in combination with nivolumab (NIVO) with or without ipilimumab (IPI) or bempegaldesleukin (BEMPEG) in patients (pts) with advanced solid tumors.

TPS4600 Background: XL092 is a novel oral inhibitor of receptor tyrosine kinases, including MET, VEGFR2, and TAM kinases (AXL, MER), which are implicated in tumor growth, metastasis, angiogenesis, and immune suppression of the tumor microenvironment. XL092 has a relatively short half-life (̃21h) to support convenient daily dosing and help manage tolerability. Preclinical studies of XL092 with an anti‒PD-1 immune checkpoint inhibitor (ICI) demonstrated antitumor activity in tumor models, and BEMPEG (IL-2 pathway agonist) showed synergy with anti‒PD-L1 and anti‒CTLA-4 agents. This phase 1b trial will evaluate the safety and clinical activity of XL092 alone and in combination with NIVO (anti‒PD-1 mAb) ±IPI (anti‒CTLA-4 mAb) or ±BEMPEG in pts with advanced solid tumors including genitourinary cancers. Presented here is the study design. Methods: This multicenter phase 1b, open-label study (NCT05176483) will enroll pts with unresectable advanced or metastatic solid tumors in dose-escalation and expansion stages. In the dose-escalation stage, ̃36 pts will be enrolled in three XL092 combination therapy cohorts using a rolling 6 design. Cohort A: XL092 (starting dose [SD] 100 mg PO QD) + NIVO (360 mg IV Q3W); Cohort B: XL092 (SD 80 mg PO QD) + NIVO (3 mg/kg IV Q3W × 4, then 480 mg IV Q4W) + IPI (1 mg/kg Q3W × 4); Cohort C: XL092 (SD 100 mg PO QD) + NIVO (360 mg IV Q3W) + BEMPEG (0.006 mg/kg IV Q3W). The primary objective of the dose-escalation stage is to determine the recommended doses of XL092 with the NIVO regimens to be used in the expansion stage. The expansion stage will include cohorts of advanced genitourinary tumors: Cohort 1, clear-cell renal cell carcinoma (ccRCC), no prior systemic therapy; Cohort 2, ccRCC, 1 prior ICI combination regimen; Cohort 3, metastatic castration-resistant prostate cancer (mCRPC), 1 prior novel-hormonal therapy; Cohort 4, urothelial carcinoma (UC), 1 prior platinum-based regimen, ICI-naïve; Cohort 5, UC, ≤2 prior systemic regimens, ICI-experienced; Cohort 6, non-ccRCC, no prior systemic therapy. In each cohort, pts will be randomized to one of the following treatments (based on tumor cohort): single-agent XL092 (Cohorts 2‒6); XL092+NIVO (Cohorts 1‒6); NIVO+IPI (Cohort 1); XL092+NIVO+IPI (Cohorts 1, 3, 6); NIVO+BEMPEG (Cohort 1), XL092+NIVO+BEMPEG (Cohort 1, 2, 4‒6). Thirty pts will be enrolled in each single-agent XL092 arm and 40 pts in each combination therapy arm. Expansion stage objectives are to assess preliminary efficacy, safety, and pharmacokinetics of XL092 alone or in combination in each tumor-specific cohort. Primary efficacy endpoints include objective response rate by investigator per RECIST v1.1 and progression-free survival by blinded independent radiology committee per Prostate Working Group 3 criteria (mCRPC cohort only). The study is currently enrolling pts. Clinical trial information: NCT05176483.

Biomarker associations of immune checkpoint inhibitor versus chemotherapy effectiveness in first-line metastatic endometrial carcinomas: A real-world study.

5596 Background: Limited evidence exists comparing outcomes of single-agent anti-PD1 immune checkpoint inhibitors (ICPI) vs. chemotherapy in the 1st line among metastatic endometrial carcinoma (mEC) patients. dMMR, MSI status, and Tumor Mutational Burden (TMB) have been characterized as predictive biomarkers of ICPI response in many solid tumors, including mEC. We sought to evaluate ICPI vs. chemotherapy effectiveness in 1st line mEC, stratified by TMB ≥ 10 mut/MB and MSI as assessed by next-generation sequencing. Methods: Following a prespecified analysis plan, this study used the nationwide (̃280 US cancer clinics) de-identified, EHR-derived, Flatiron Health-Foundation Medicine mEC clinico-genomic database (FH-FMI CGDB), with tissue CGP between 1/2011 - 6/2021. Cohort inclusion criteria: recurrent mEC patients with stage I-III at original diagnosis, 1st line ICPI or platinum chemotherapy treatment with TMB and MSI assessments available. Adjusted hazard ratios (aHR) from multivariable Cox proportional hazard models were utilized for time to next treatment (TTNT) and overall survival (OS) comparisons between 1L chemotherapy and 1L ICPI from start of 1L treatment stratified by TMB (≥ 10 vs. < 10) and adjusted for ECOG, BMI, and stage at diagnosis. Results: Among the 1st line cohort, patients received either Chemotherapy (n = 139, 87%) or first-line ICPI (n = 20, 13%). While the overlap between the TMB ≥ 10 (n = 46) population and MSI-H (n = 39) populations was high, with 38/46 (83%) of TMB ≥ 10 classified as MSI-H and 38/39 (97%) of MSI-H with a TMB ≥ 10, there were also 8 (17%) TMB ≥ 10 patients who were MSS. TMB ≥ 10 was associated with more favorable TTNT (aHR: 0.11 [0.03 - 0.44]) and OS (aHR: 0.1 [0.01 - 0.82]) on single-agent ICPIs vs. chemotherapy; however, TMB < 10 patients exhibited no observed differences in TTNT (aHR: 1.66 [0.79 - 3.48]) or OS (aHR: 1.79 [0.66 - 4.8]) between treatments. MSI-H pts were associated with more favorable TTNT (aHR: 0.1 [0.02 - 0.39]) and OS (aHR: 0.1 [0.01 - 0.86]) on single-agent ICPIs over chemotherapy; however, MSS pts did not observe differences in TTNT (aHR: 1.5 [0.65 - 3.5]) or OS (aHR: 2.14 [0.63 - 7.26]) between ICPI vs. chemotherapy. Conclusions: Recurrent 1st line mEC patients with TMB ≥ 10 and/or MSI-H exhibit more favorable outcomes on single-agent ICPI than standard chemotherapy in real-world settings. These findings warrant prospective randomized validation. Future studies should assess the utility of a combined biomarker approach across TMB and MSI status to identify the broadest group of patients who might benefit from ICPI.

High glucose drinks improve the anti-tumor efficacy of brain tumor immunity by gut microbiome modulation

Abstract Over the past decades, consumption of high sugar drinks has been linked to diverse diseases such as obesity, high blood pressure and diabetes. It has been found that most of these high sugar drinks have negative effect on the host including progression of colorectal malignancies. However, there were little literatures about the effect of intake of these high sugar drinks on distant tumors such as glioblastoma (GBM). We observed the GBM survival rate by supplying 20% glucose water in the GL261 mouse syngeneic GBM model and found consumption of high glucose water increased the survival outcomes. Administration of such high glucose water enhances the anti-tumor efficacy of CD8+ T cells in GBM tumor microenvironment. This change induced a synergistic effect with anti PD-1 immune checkpoint inhibitor in GBM mouse syngeneic model. We found that the gut microbiota induced the anti-tumor effect of high glucose water with negative result of germ-free mice experiment. Through 16S rRNA sequencing analysis of fecal samples of mice, administration of high glucose water induced more abundance of Desulfovibrio genus and proved that this strain played a decisive role in improving the survival rate of the GBM mouse model. As a result, we identified that the intake of high sugar drinks could affect the survival rate of GBM through changes in gut microbiome.

Tumor-immune microenvironment revealed by Imaging Mass Cytometry in a metastatic sarcomatoid urothelial carcinoma with a prolonged response to pembrolizumab.

Sarcomatoid urothelial carcinoma (SUC) is a rare subtype of urothelial carcinoma (UC) that typically presents at an advanced stage compared to more common variants of UC. Locally advanced and metastatic UC have a poor long-term survival following progression on first-line platinum-based chemotherapy. Antibodies directed against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1) are now approved to be used in these scenarios. The need for reliable biomarkers for treatment stratification is still under research. Here, we present a novel case report of the first Imaging Mass Cytometry (IMC) analysis done in SUC to investigate the immune cell repertoire and PD-L1 expression in a patient who presented with metastatic SUC and experienced a prolonged response to the anti-PD1 immune checkpoint inhibitor pembrolizumab after progression on first-line chemotherapy. This case report provides an important platform for translating these findings to a larger cohort of UC and UC variants.

Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors

Chemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal response remain elusive. To date, most studies have focused on tumor-intrinsic properties that render them “immune-excluded”. Here, we explore an alternative, drug-induced mechanism that impedes therapeutic response via disrupting the onset of immunogenic cell death. Using two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC), we show that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constraines their antitumoral activity, despite expression of activation markers IFNγ and granzyme B. Mechanistically, chemotherapy induces the release of prostaglandin E2 (PGE2) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE2 release, CD8+ T cells become tumoricidal and display an intraepithelial-infiltrating (or inflamed) pattern. This “iDAMP blockade” approach synergizes with chemotherapy and sensitizes bladder tumors towards anti-PD1 immune checkpoint inhibitor therapy. These findings provide a compelling rationale to evaluate this drug combination in future clinical trials.

A single-arm phase II study of cabozantinib and atezolizumab in patients with recurrent or metastatic esophageal squamous cell carcinoma (R/M ESCC) who failed platinum-based chemotherapy.

TPS364 Background: Patients with R/M ESCC failing platinum-based chemotherapy have grave prognosis. Anti PD-1 immune-checkpoint inhibitors (ICIs), by demonstrating survival benefits over 2nd-line chemotherapy in multiple phase III trials, have emerged as a new standard-of-care for patients with platinum-refractory R/M ESCC. However, the efficacy of anti-PD-1 ICIs remains modest with an objective response rate (ORR) of 17-20%; and the median overall survivals (OS) for these patients range from 8.2 to 10 months. Cabozantinib, a multikinase inhibitor, in combination with atezolizumab has been investigated in the phase Ib COSMIC-021 trial, which includes multiple cohorts of various cancer types including gastroesophageal cancer and head-and-neck cancer. Promising preliminary results were reported in lung cancer and genitourinary cancer cohorts. To investigate the combination of cabozantinib plus atezolizumab in patients with ESCC, a subtype of esophageal cancer that may be under-represented in the gastroesophageal cancer cohort of COSMIC-021 trial, we thus proposed this phase II trial to verify the hypothesis whether adding cabozantinib to atezolizumab would improve the outcomes of R/M ESCC patients who have failed platinum-based chemotherapy. Methods: This single institution single-arm phase II study includes patients with histologically confirmed R/M ESCC who failed at least one platinum-based chemotherapy. Patients with prior exposure of any ICI or kinase inhibitor are excluded. Patients enrolled will receive cabozantinib 40mg once per day and atezolizumab 1200mg once every three weeks until disease progression or intolerable toxicities. The primary endpoint of this study is the ORR evaluated by RECIST 1.1; and the key secondary endpoints include progression-free survival, OS, and toxicity profile. We hypothesize that combination of cabozantinib plus atezolizumab will improve the ORR from 15% to 30%. With one-sided, 0.1 type I error (α), 0.2 type II error (β, corresponding power: 0.8), the sample size will be 37. The study, registered with clinical trial ID of NCT05007613, started patient enrollment in Jun 2021. As of Sep of 2021, 5 patients have been enrolled. Clinical trial information: NCT05007613.

Outcome of Relapsed/Refractory Aggressive B-Cell Lymphoma Patients Relapsing after Anti-CD19 CAR T-Cells and Enrolled in the Descar-T French National Registry

Background. Anti-CD19 Chimeric Antigen Receptor (CAR) T-cells are a major therapeutic advance in the management of patients (pts) with relapsed/refractory aggressive B-cell lymphoma (R/R aggressive BCL) with reported overall response rates between 40% and 83% in the pivotal trials (ZUMA1, JULIET, TRANSCEND) as well as in the real-life cohorts with either axicabtagene ciloleucel (axi-cel, Yescarta) or tisagenlecleucel (tisa-cel, Kymriah). However, a significant number of pts will experience progression or relapse after infusion with an estimated 24-month progression-free survival (PFS) of between 33% and 42%. DESCAR-T is a nationwide registry that aims to collect real-life data for all pts treated with commercialized CAR T-cells in France. It represents a unique opportunity to investigate the outcome of pts who relapse after CAR T-cell therapy.Patients and Methods. In all, 680 pts with R/R aggressive BCL were registered in DESCAR-T from August 2018 and 550 were infused at the time of the present analysis (April 12, 2021) with either axi-cel (n=350) or tisa-cel, n=200). All pts gave informed informed consent before DESCAR-T registration. Progression and relapse after CAR T-cells were defined based on the Cheson 2014 response assessment criteria.Results. With a median follow-up (F-up) of 7.9 months, 238 pts (43.3%) out of 550 treated pts relapsed, after axi-cel in 136 pts (F-up = 9.0 months [5.1 - 9.7]) and after tisa-cel in 102 pts (F-up = 7.8 months [5.9 - 10.4]). Histological subtypes were DLBCL (n 178, 74.8%), PMBL (n=11, 4.6%), HGBCL (n= 3, 1.3%), transformed follicular lymphoma (tr FL) (n=31, 13%), or other histologies (FL n=2, PCNSL n=1, tr MZL n=3, unclassifiable hodgkin/DLBCL n=9). At time of registration, median age was 62 years (range 18;77), 43.6% were aged >65 yrs, and 67.2% were male; 184 (79.7%) presented with advanced disease (stage III or IV), and 13 (5.9%) with low age-adjusted International Prognostic Index (aaIPI), 82 (37.1%) with low-intermediate aaIPI, 110 (49.8%) with high-intermediate aaIPI, and 16 (7.2%) with high aaIPI. At time of CAR T-cell infusion, 36 (18.9%) pts presented with ECOG PS >=2 and 72 (38.9%) with an elevated LDH level. The median number of lines prior to CAR T-cell infusion was 3 (range 2-9), including 48 (20.1%) transplant (46 auto-HSCT and 2 allo-HSCT). Median time between order and infusion was 50 days (IQR 43; 59). Bridging therapy was administered to 87.8% of the pts, with a high-dose regimen including combined immunochemotherapy for 84.5% of the pts. Failure after CAR T-cells occurred after a median time of 2.71 months (range 0.2; 21.5), 54 (22.7%) being during the first month after infusion (< M1) and 156 (65.5%) during the first-three months after infusion (<M3). At failure, 154 (64%) patients received treatments that maybe combined and described as followed : 70 (45.5%) lenalidomide, 70 (45.5%) various immunotherapies (rituximab, daratumomab, polatuzumab), 31 (20.1%) a combined immunochemotherapy with various regimens (R-DHAX, RICE, Pola-R-Benda,...), 21 (13.6%) an anti-PD1 immune checkpoint inhibitor (Nivolumab, pembrolizumab), 11 (7.1%) bi-specific T-cell engagers (TCE), 18 (11.7%) radiotherapy, and 3 a transplant (1 an auto-HSCT and 2 an allo-HSCT). The overall response rate to the salvage therapy after CAR T-cells was 11% (complete response rate 5.2%). The median PFS was 2.8 months (95% CL, 2.4 -3.1). The median overall survival (OS) was 5.2 months (95% CL, 4.1- 6.6) (Figure 1A). The median OS was even shorter in pts who failed during the first month (1.9 months [95% CL, 1.1- 3.2] vs 6.7 months [95 CL 5.5 : 9.3] p<0.0001) (Figure 1B). 26.9% of the pts in the overall cohort were alive at 6 months, but only 18.9% were alive in the group of pts relapsing during the first month. In multivariate analysis, predictors of OS were high LDH level at time of infusion, time to failure < 1 month after CAR T-cells, no access to immuno-oncology treatment such as TCE or lenalidomide.Conclusion. This study is the first analysis reporting the outcome of patients with R/R aggressive BCL relapsing after anti-CD19 CAR T-cells. These results demonstrate the poor outcome of these pts and identifies the need for further innovative treatment strategies.Figure1. Overall survival from the CAR T-cell infusion in patients with R/R LBCL relapsing after CAR T-cells. (A) overall population. (B) according to the interval between CAR T-infusion and relapse (< 1 month and > 1 month) [Display omitted] DisclosuresDi Blasi: Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Le Bras: Takeda: Honoraria, Research Funding; Kite Gilead: Honoraria; Novartis: Honoraria; Celgene BMS: Research Funding. Feugier: Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria. Casasnovas: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Mohty: Amgen: Honoraria; Jazz: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Adaptive Biotechnologies: Honoraria. Sesques: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Chugai: Honoraria. Morschhauser: Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees.