PD-1 Checkpoint Inhibitors Research Articles

Real-world study of chemotherapy plus immunotherapy versus chemotherapy alone as neoadjuvant treatment guided bladder-sparing therapy for localized muscle-invasive bladder cancer.

499 Background: Bladder-preserving combined-modality therapy has been a popular research field as an alternative to radical cystectomy for selected patients with localized muscle-invasive bladder cancer (MIBC). This real-world study aimed to compare the efficacy of neoadjuvant chemotherapy plus immunotherapy versus chemotherapy alone as one of bladder-sparing therapies for localized MIBC. Methods: Patients with cT2-4bN0-3M0-1a pathological and imaging diagnosed MIBC were included in the study. Either chemotherapy (gemcitabine and cisplatin/carboplatin) plus immunotherapy (PD-1 checkpoint inhibitor, including pembrolizumab，tislelizumab and toripalimab) or chemotherapy alone were given as patients’ wish. The primary endpoint was complete response rate (CR, T0/Ta/Tis), and the secondary endpoints were disease control rate (DCR), progression-free survival (PFS), bladder-intact disease-free survival (BI-DFS) and toxicity. Results: In total, 41 patients were included, 25 in combination group and 16 in chemotherapy group respectively. The baseline characteristics were well balanced in two groups. Median follow-up time was 15.3 ±4.4 months(m). No patient died. The efficacy evaluable population was consisted of 34 pts (22 in combination group; 12 in chemotherapy alone group). The CR rate for combination group was 50.0% and 0 for chemotherapy alone group. One patient suffered from disease progression in combination group and three in chemotherapy group. The DCRs for combination group and chemotherapy group were 95.5% and 66.7%, respectively ( p= 0.003). Twelve patients had radiotherapy and six patients had radical cystectomy followed by neoadjuvant treatments in combination group. And two patients had radiotherapy and three patients had radical cystectomy in chemotherapy group. The one-year PFS rates were 95.5% and 62.5% for combination group and chemotherapy group( p= 0.010), and the one-year BI-DFS were 66.1% versus 27.5% respectively( p= 0.159). The bladder-preserving combined-modality therapies used were well-tolerated with acceptable and manageable toxicities. Grade ¾ hematological system adverse events were 15.9% and 6.4% in combination group and chemotherapy group, respectively ( p= 0.021). Conclusions: Neoadjuvant chemotherapy plus immunotherapy showed better efficacy compared with chemotherapy alone as an important bladder-sparing therapy for locally advanced MIBC with acceptable and manageable toxicities.

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial.

Simple SummaryOptimal dosing and duration of adjuvant treatment with PD-1 immune checkpoint inhibitors in melanoma patients have not been established. The investigated low-dose regimen of nivolumab with or without ipilimumab (in a sequential dual-cohort phase II trial), resulted in a 12-months relapse-free survival (RFS) rate and tolerability that was comparable to what has been served with standard dosing of nivolumab or pembrolizumab when patients were matched for stage. The incidence of immune-related adverse events was similar to what has been reported from registration trials in this indication. Immunohistochemical quantification of intra- and peritumoral immune cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. Therefore, low-dose regimes of PD-1 blocking monoclonal antibodies deserve further study as cost-effective alternatives for currently approved standard dosing regimens, with baseline immunohistochemical tumor profiling to be further explored as a promising biomarker.Background: Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial. Methods: Following the complete resection of melanoma metastases, patients were treated with a single fixed dose of ipilimumab (50 mg) plus 4 bi-weekly fixed doses of nivolumab (10 mg) (cohort-1), or nivolumab for 1 year (10 mg fixed dose, Q2w x9, followed by Q8w x4) (cohort-2). Twelve-months relapse-free survival (RFS) served as the primary endpoint. Results: After a median follow-up of 235 weeks for cohort-1 (34 patients), and 190 weeks for cohort-2 (21 patients), the 12-months RFS-rate was, respectively, 55.9% (95% CI, 39–72), and 85.7% (95% CI, 70–100). Treatment-related adverse events occurred in 27 (79%), and 18 (86%) patients, with 3 (9%), and 1 (5%) grade 3 adverse events in cohort-1 and -2, respectively. Immunohistochemical quantification of intra- and peritumoral CD3+ T cells and CD20+ B cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. Conclusions: One year of adjuvant low-dose nivolumab could be an effective and economically advantageous alternative for standard dosing, at the condition of further confirmation in a larger patient cohort. A shorter low-dose nivolumab plus ipilimumab regimen seems inferior and less tolerable.

Efficacy of immunotherapy beyond RECIST progression in advanced melanoma: a real-world evidence.

Immunotherapy (ITH) holds the possibility of tumor burden decrease after initial RECIST 1.1 defined progression. The clinical concept of treating selected patients (pts) beyond disease progression (PD) is supported by so-called pseudoprogression phenomenon. The aim of this study was to evaluate real-life practice and outcomes related to treatment beyond (RECIST) progression (TBP) in advanced melanoma patients. Of 584 subsequent melanoma pts analyzed 77 (13.2%) received TBP. In this cohort, the median time to first PD (TTFP) was 5.29months (m), while time to second PD (TTSP)-8.02m. On TBP 23.4% pts achieved an objective response (OR), and next 42.9%-stabilization of the disease (SD). 1st PD was reported most often as the development of a new lesion or increase (> 20%) of the diameter of three or more targets. In about 50% second PD was observed as an increase in the diameter of different targets that in 1st PD. Multimodal treatment resulted in 9.82m TTSP, while ITH alone-4.93m (p = 0.128). An oligoprogressive pattern of first PD was associated with longer TTSP (HR 0.55, 95% CI: 0.32-0.94). Median OS after first PD was 28.75months and correlated with OR during TBP (HR 0.18, 95% CI: 0.004-0.76). Selected clinically fit melanoma patients, despite evidence of first radiographic progression, may benefit from continued treatment with PD-1 checkpoint inhibitors, but the findings should be validated in larger prospective trials. Multidisciplinary treatment should be offered to advanced melanoma patients, including radiosurgery or stereotactic radiotherapy of single loci progressing during immunotherapy.

CDKN2A-positive melanoma patient treated with combination immunotherapy – A case report

Germline aberrations in the CDKN2A gene are observed in 20%–40% of families susceptible to melanoma. Positive CDKN2A status is associated with early age of onset of melanoma, multiple primary melanomas, and pancreatic cancer. We report here a melanoma patient with a germline mutation c.68G>A p.(Gly23Asp) in CDKN2A who had a history of multiple cutaneous melanomas and a family history consistent with familial atypical multiple mole melanoma (FAMMM) syndrome. He developed oligometastatic disease with BRAF-positive melanoma metastases in soft tissue and gallbladder and was treated with surgical resection followed by combination therapy of PD-1 and CTLA-4 immune checkpoint inhibitor, which resulted in good remission. Molecular analysis of all primary melanomas and both metastatic sites revealed the same BRAF c.1799T>A p.(Val600Glu) V600E mutations.

Emerging Evidence from Landmark Clinical Trials on Perioperative Immunotherapy in Resectable Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) remains one of the most prevalent cancers worldwide, with high rates of local and distant recurrence limiting survival even after curative-intent surgical resection. Traditional adjuvant chemotherapy benefits only 5% of patients, and as such additional treatment modalities are urgently needed to improve NSCLC patient outcomes. Systemic therapy with PD1 and PDL1 immune check-point inhibitors (ICIs) has emerged as a promising treatment option in many types of solid malignancies, including lung cancer. Encouraging results from immunotherapy trials in metastatic lung cancer populations, and now newer results from ongoing clinical trials in early stage locally advanced lung cancers, suggested an evolving role for perioperative immune checkpoint inhibition in resectable NSCLC. In this review we examine the latest advances in the landscape of clinical trials on immunotherapy in resectable NSCLC. We discuss the key findings and specific clinical challenges related to neoadjuvant administration of these immune therapies in the CheckMate816, Impower030, AEGEAN and KEYNOTE671 phase III clinical trials. The role of adjuvant ICI is also discussed examining the ANVIL, Impower010, and PEARLS trials. By understanding the remaining unanswered questions and clinical dilemmas that exist in this rapidly evolving field for ICIs in early stage NSCLC, clinicians may provide patients options which may markedly improve survival outcomes for this life-threatening disease.

Retrospective analysis of immune-related adverse events of the immune checkpoint inhibitors of PD-1/PD-l1 in the Fujian provincial hospital

Introduction: The effectiveness of programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) on tumor has been reported. However, the immune-related adverse events (irAEs) and its clinical management of the immune checkpoint inhibitors (ICIs) have not been fully understood. We aimed to analyze the irAEs and its ICIs targeting the PD-1/PD-L1. Methods: The retrospective analysis was performed on the irAEs of cancer patients treated with anti-PD1/PD-L1 monoclonal antibodies from January 2020 to August 2021 including 240 patients/547 cycles. The following aspects including the categories and the grades of the adverse events (AEs), the time of onset and duration, management plan, and prognosis were evaluated. Results: Among 240 patients, 93 patients (38.75%) experienced irAEs, and 10 patients (4.16%) had AEs that involved multiple organ systems at the same time. There were 83 cases (34.58%) of grade 1–2 AEs and 10 cases (4.17%) of grade three and above AEs. AEs above grade three included five cases of grade three AEs (3 cases of hepatic toxicity, one case of colitis, and one case of skin toxicity), three cases of grade four AEs (pneumonia); and 2 cases of grade five AEs (two deaths due to pneumonia). The complete remission of AEs was achieved in 10 patients by corticosteroid impulse therapy, maintenance therapy, and symptomatic therapy. Among them, six cases continued to use anti-PD1/PD-L1 monoclonal antibodies, two cases stopped, and two patients died from systemic multi-organ failure due to the delayed observation of autoimmune pneumonia. IrAEs occurred at different times and durations in different systems or organs. Conclusion: The safety of PD-1/PD-L1 inhibitors was approved in clinical applications. The prevalence of grade three and above AEs is relatively low. Timely diagnosis and early glucocorticoid therapies are adequate and effective approaches for the management of irAEs.

Detection of temozolomide-induced hypermutation and response to PD-1 checkpoint inhibitor in recurrent glioblastoma.

BackgroundDespite aggressive upfront treatment in glioblastoma (GBM), recurrence remains inevitable for most patients. Accumulating evidence has identified hypermutation induced by temozolomide (TMZ) as an emerging subtype of recurrent GBM. However, its biological and therapeutic significance has yet to be described.MethodsWe combined GBM patient and derive GBM stem cells (GSCs) from tumors following TMZ to explore response of hypermutant and non-hypermutant emergent phenotypes and explore the immune relevance of hypermutant and non-hypermutant states in vivo.ResultsHypermutation emerges as one of two possible mutational subtypes following TMZ treatment in vivo and demonstrates distinct phenotypic features compared to non-hypermutant recurrent GBM. Hypermutant tumors elicited robust immune rejection in subcutaneous contexts which was accompanied by increased immune cell infiltration. In contrast, immune rejection of hypermutant tumors were stunted in orthotopic settings where we observe limited immune infiltration. Use of anti-PD-1 immunotherapy showed that immunosuppression in orthotopic contexts was independent from the PD-1/PD-L1 axis. Finally, we demonstrate that mutational burden can be estimated from DNA contained in extracellular vesicles (EVs).ConclusionHypermutation post-TMZ are phenotypically distinct from non-hypermutant GBM and requires personalization for appropriate treatment. The brain microenvironment may be immunosuppressive and exploration of the mechanisms behind this may be key to improving immunotherapy response in this subtype of recurrent GBM.

Limbic encephalitis in metastatic malignant melanoma patient induced by PD-1 checkpoint inhibitor pembrolizumab

This case report presents a patient with metastatic malignant melanoma who was treated with immunotherapy with the PD-1 checkpoint inhibitor pembrolizumab and developed a rare neurological immune-related adverse event (irAE) limbic encephalitis. Despite successful treatment of irAE, the neurological deficit persisted. With this article, we would like to make all physicians aware of this rare but serious irAE that can occur at any time during treatment with a checkpoint inhibitor.

Anti–PD-1 Antibody Combined with Drug-eluting Bead Transarterial Chemoembolization for Barcelona Clinic Liver Cancer Stage A/B Hepatocellular Carcinoma Beyond the Milan Criteria

Introduction: The aim of this study was to investigate the potential value of the combined drug-eluting bead (DEB)-TACE and anti–PD-1 antibody (Sintilimab) as preoperative treatment for patients with Barcelona Clinic Liver Cancer (BCLC) Stage A/B HCC beyond the Milan Criteria. Methods: This is a prospective phase II pilot study involving patients with BCLC stage A/B HCC beyond the Milan criteria. DEB-TACE therapy was started together with the first dose of Sintilimab (200mg every three weeks). Repeated TACE was performed on demand. Safety and tumor response were routinely assessed, and further decisions were made in a multidisplinary manner. If necessary, surgical resection occurs within 8 weeks after the last DEB-TACE treatment. Results: Sixty-one patients—of whom 52.5% had BCLC stage B disease— underwent 144 cycles of therapy (DEB-TACE in combination with Sintilimab, 73 cycles; Sintilimab alone, 71 cycles). The median number of DEB-TACE sessions per patient was two (range, one to three cycles), and the median doses of Sintilimab was 400 mg. Commonly reported adverse events included alterations of liver function (90.2%), fatigue (52.4%), pain (49.2%), the majority of which were grades 1-2. Objective response was observed in 36/60 evaluable patients using mRECIST criteria. 51 patients proceeded with surgical resection as judged by a multidisplinary team, and 47.9% of patients experienced major pathologic response (MPR) by pathological examination. Conclusion: The combination of PD-1 checkpoint inhibition and DEB-TACE is safe and effective as preoperative treatment in patients with BCLC A/B HCC beyond the Milan Criteria.

A Possible Abscopal Effect Of Radioimmunotherapy in a Patient With Advanced Oligometastatic Adenocarcinoma of the Lung

"Two randomized phase III studies provided cumulated long-term results, comparing second line treatment with Nivolumab versus Docetaxel in advanced non-small cell lung cancer (NSCLC). With the advent of modern immunotherapy (IO), the potential for even more immune activation by radiation therapy, inducing tumor specific immunity led to a novel role for radiotherapy in systemic disease. This case proposes to evaluate the benefit of second line immunotherapy with Nivolumab, a PD-1 checkpoint inhibitor, and hypofractionated radiotherapy, in a patient with advanced oligometastatic adenocarcinoma of the lung, with progressive disease after first line chemotherapy, and the analysis of a possible abscopal effect. A 50-year-old male, heavy smoker with a 30 years-pack index, presented with a history of left posterior thoracic pain. MRI identified an osteolytic lesion on the 10th rib and CT scan showed an additional 25 mm nodule in the left upper lobe (LUL) and a 7 mm nodule in the left lower lobe (LLL). Atypical resections of the nodules and resection of the osteolytic lesion of the rib were performed. The pathological examination revealed a G2 adenocarcinoma of the lung (ALK and EGFR negative) pT4Nx pM1 with metastases in the rib and pleura, with unspecified margins. Chemotherapy was administered, with complete response on imaging after 6 cycles of Gemcitabine/Carboplatin, and hematologic toxicity. After 7 ½ months a regional and distant progression of the disease with metastases on the 7th and 10th rib was revealed on PET-CT. Palliative hypofractionated radiotherapy was administered to a dose of 20 Gy/ 5 fr to the painful 7th rib metastasis and the patient started second line treatment with Nivolumab, 240 mg iv q2wks. Three years later, at his last follow-up in Nov 2021, the patient maintains a (PET)-CT complete response, with no adverse events. A possible abscopal effect may be suspected in this case."

Anlotinib Induces a T Cell-Inflamed Tumor Microenvironment by Facilitating Vessel Normalization and Enhances the Efficacy of PD-1 Checkpoint Blockade in Neuroblastoma.

Anlotinib has achieved good results in clinical trials of a variety of cancers. However, the effects of anlotinib on the tumor microenvironment (TME) and systemic immunity have not been reported. There is an urgent need to identify the underlying mechanism to reveal new opportunities for its application in neuroblastoma (NB) and other cancers. Understanding the mechanism will hopefully achieve the goal of using the same method to treat different cancers. This study used bioinformatics, NB syngeneic mouse models, flow cytometry, RNA-seq, and immunofluorescence staining to explore the mechanisms of anlotinib on the TME, and further explored anlotinib-containing combination treatment strategies. We proved that anlotinib facilitates tumor vessel normalization at least partially through CD4+ T cells, reprograms the immunosuppressive TME into an immunostimulatory TME, significantly inhibits tumor growth, and effectively prevents systemic immunosuppression. Moreover, the combination of anlotinib with a PD-1 checkpoint inhibitor counteracts the immunosuppression caused by the upregulation of PD-L1 after monotherapy, extends the period of vascular normalization, and finally induces NB regression. To our knowledge, this study is the first to dynamically evaluate the effect of a multitarget antiangiogenic tyrosine kinase inhibitor on the TME. These findings have very important clinical value in guiding the testing of related drugs in NB and other cancers. Based on these findings, we are conducting a phase II clinical study (NCT04842526) on the efficacy and safety of anlotinib, irinotecan, and temozolomide in the treatment of refractory or relapsed NB, and hopefully we will observe patient benefit.

Transcriptomic Features of Immune Exhaustion and Senescence Predict Outcomes and Define Checkpoint Blockade-Unresponsive Microenvironments in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. Reinstating immunological control of AML is highly desirable to eradicate chemotherapy-resistant clones and provide long-term disease control. We recently identified bone marrow (BM) microenvironmental transcriptomic profiles that stratify patients with newly diagnosed AML into an immune-infiltrated and an immune-depleted subtype and that refine the accuracy of survival prediction beyond that afforded by current prognosticators (Vadakekolathu J et al., 2020). We have also shown that CD8 + T cells from patients with AML exhibit features of immune exhaustion and senescence (IES), including heightened expression of killer cell lectin-like receptor subfamily G member 1 (KLRG1) and B3GAT1 (encoding CD57) (Knaus H et al., 2018). Whether deranged T-cell functions affect the likelihood of responding to antitumor therapy, including immune checkpoint blockade (ICB), is an outstanding question in AML.In the current study, we analyzed 183 BM samples collected longitudinally at time of AML onset, response assessment and disease relapse from multiple cohorts of patients with AML treated with standard-of-care induction chemotherapy, and from 33 elderly AML patients with newly diagnosed or chemotherapy-refractory/relapsed AML treated with azacitidine, and the PD-1 checkpoint inhibitor pembrolizumab (NCT02845297). Primary patient specimens and associated clinical data were obtained via informed consent in accordance with the Declaration of Helsinki on research protocols approved by the Institutional Review Boards of the participating Institutions. RNA (150-200 ng) was extracted from BM aspirates and was processed on the nCounter FLEX analysis system (NanoString Technologies, Seattle, WA) using the PanCancer Immune profiling panel, as previously published (Vadakekolathu J et al., 2020). The correlation between transcriptomic features of IES, clinical characteristics, therapeutic response and patient outcome was validated using publicly available RNA-sequencing and NanoString data from 1,698 patients with AML, including samples from the TCGA-AML (n=147 cases), Beat-AML Master Trial (n=264 cases, of which 240 with survival data and 195 with chemotherapy response data) and Children's Oncology Group (COG)-TARGET AML series (n=145 cases).We initially showed that, compared with their non-senescent CD8 +CD57 -KLRG1 - counterpart, senescent CD8 +CD57 +KLRG1 + T cells are functionally impaired in terms of their ability to effect AML-blast killing mediated by an anti-CD33/CD3 bi-specific T-cell engager antibody construct (kindly provided by Amgen, USA; effector/target [E/T] ratio = 1:5). We then used gene set enrichment analysis (GSEA) to derive a transcriptomic signature of IES encompassing natural killer (NK)-cell and stem-like CD8 + T-cell markers, and showed that IES states correlate with lymphoid infiltration, adverse-risk molecular lesions (TP53 and RUNX1 mutations), experimental gene signatures of leukemia stemness (LSC17 score; Ng et al., 2016) and poor outcome in response to standard induction chemotherapy (Fig. 1A). In independent validation cohorts of children and adults with AML, the IES score was higher at baseline in patients with primary induction failure (following a standard 2 cycles of chemotherapy) compared with complete remission, increased in post-chemotherapy BM specimens, and predicted survival with greater accuracy than the ELN cytogenetic risk classifier (Fig. 1B). In the immunotherapy setting, high IES scores at baseline defined a checkpoint blockade-unresponsive AML tumor microenvironment and correlated with significantly shorter overall survival (9.1 versus 15.56 months in patients with high and low IES scores, respectively; HR = 3.32 (95% CI = 1.19-9.25); log-rank P = 0.021; Fig. 1C). Finally, the IES-related gene set also predicted for long-term outcomes and objective responses, based on RECIST criteria, to single-agent nivolumab or pembrolizumab, or combination anti-PD-1 + anti-CTLA-4, in 106 patients with melanoma (PRJEB23709 and GSE93157 series), a tumor type known to derive durable clinical benefit from ICB (Fig. 1D).Our findings encourage the pursuit of immune senescence reversal as a strategy to functionally reinvigorate T cells and could inform the delivery of ICB and other T cell-targeting immunotherapies to patients who are likely to benefit. [Display omitted] DisclosuresRadojcic: Syndax Pharmaceuticals: Research Funding; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Allakos: Membership on an entity's Board of Directors or advisory committees. Minden: Astellas: Consultancy. Tasian: Aleta Biotherapeutics: Consultancy; Gilead Sciences: Research Funding; Kura Oncology: Consultancy; Incyte Corporation: Research Funding.

Infectious Complications Among Patients With AML Treated With Immune Checkpoint Inhibitors

BackgroundThe incidence and spectrum of infections in acute myeloid leukemia (AML) patients treated with immune checkpoint inhibitors (CPIs) in combination with a hypomethylating agents (HMAs) is not known. Nivolumab is a PD-1 checkpoint inhibitor approved in many solid tumors and lymphoma. Materials/MethodsWe performed a retrospective cohort study of 75 adult patients at MD Anderson Cancer Center with relapsed/refractory AML treated with azacitidine and nivolumab or with nivolumab and ipilimumab from March 2016 through March 2020 and described the infectious complications that occurred during their treatment. ResultsSixty-four (85%) patients developed an infection during the study period, and bacterial infections were by far the most common type of infection. A comparison of risk factors and characteristic between the 75 patients on CPIs who developed infection and those who did not found that corticosteroid use (odds ratio [OR], 28; 95% confidence interval [CI], 1.6-490; P =.02) and lymphopenia (OR, 4; 95% CI, 1-15.5; P =.04) were significantly associated with infections. ConclusionPatient with relapsed/refractory AML treated with salvage CPI-based therapy were more likely to develop infections when treated with corticosteroids in the setting of an immune-related adverse event, compared to those who were not.

Tumor Microenvironment Profiles Reveal Distinct Therapy-Oriented Proteogenomic Characteristics in Colorectal Cancer.

Advances in immunotherapy have made an unprecedented leap in treating colorectal cancer (CRC). However, more effective therapeutic regimes need a deeper understanding of molecular architectures for precise patient stratification and therapeutic improvement. We profiled patients receiving neoadjuvant chemotherapy alone or in combination with immunotherapy (PD-1 checkpoint inhibitor) using Digital Spatial Profiler (DSP), a high-plex spatial proteogenomic technology. Compartmentalization-based high-plex profiling of both proteins and mRNAs revealed pronounced immune infiltration at tumor regions associated with immunotherapy treatment. The protein and the corresponding mRNA levels within the same selected regions of those patient samples correlate, indicating an overall concordance between the transcriptional and translational levels. An elevated expression of PD-L1 at both protein and the mRNA levels was discovered in the tumor compartment of immunotherapy-treated patients compared with chemo-treated patients, indicating potential prognostic biomarkers are explorable in a spatial manner at the local tumor microenvironment (TME). An elevated expression of PD-L1 was verified by immunohistochemistry. Other compartment-specific biomarkers were also differentially expressed between the tumor and stromal regions, indicating a dynamic interplay that can potentiate novel biomarker discovery from the TME perspectives. Simultaneously, a high-plex spatial profiling of protein and mRNA in the tumor microenvironment of colorectal cancer was performed.

Immune Checkpoint Inhibitors for Genitourinary Cancers: Treatment Indications, Investigational Approaches and Biomarkers.

Simple SummaryImmune checkpoint inhibitors (ICI) have reshaped treatment paradigms of multiple solid organ malignancies. In genitourinary malignancies (GU), ICI provide significant clinical benefit and are approved for use in localized and metastatic renal cell carcinoma and urothelial carcinoma. Investigational approaches to maximize clinical benefit and expand use of ICI across GU malignancies are actively being pursued. In addition, biomarkers predictive of clinical benefit to ICI have been identified; however, further validation and incorporation into guideline-based management remain active areas of investigation.Cancers of the genitourinary (GU) tract are common malignancies in both men and women and are a major source of morbidity and mortality. Immune checkpoint inhibitors (ICI) targeting CTLA-4, PD-1 or PD-L1 have provided clinical benefit, particularly in renal cell and urothelial carcinoma, and have been incorporated into standard of care treatment in both localized and metastatic settings. However, a large fraction of patients do not derive benefit. Identification of patient and tumor-derived factors which associate with response have led to insights into mechanisms of response and resistance to ICI. Herein, we review current approvals and clinical development of ICI in GU malignancies and discuss exploratory biomarkers which aid in personalized treatment selection.

PD-1 expression in hepatocellular carcinoma predicts liver-directed therapy response and bridge-to-transplant survival

BackgroundHepatocellular carcinoma (HCC) patients undergo liver-directed therapy (LDT) to control tumor burden while awaiting liver transplantation with response impacting waitlist survival. In this study, we investigate the link between absolute lymphocyte count (ALC) and PD-1 expression with response to LDT and bridge-to-transplant survival.MethodsTreatment-naïve HCC patients (n = 86) undergoing LDT were enrolled at a single center from August 2016–March 2020. Response to LDT was determined using mRECIST. Blood samples were collected on the day of LDT and at follow-up. Cells were analyzed for phenotype by flow cytometry. Outcomes were liver transplantation or tumor progression.ResultsIncomplete response to initial LDT was associated with tumor progression precluding liver transplantation (OR: 7.6, 1.7 – 33.3, P < 0.001). Univariate analysis of baseline T cell phenotypes revealed ALC (OR: 0.44, 0.24–0.85, P = 0.009) as well as intermediate expression of PD-1 on CD4 (OR: 3.3, 1.03–10.3, P = 0.034) and CD8 T cells (OR: 3.0, 0.99–8.8 P = 0.043) associated with incomplete response to LDT. Elevations in PD-1 expression were associated with increased risk of bridge-to-transplant tumor progression (HR: 3.2, 1.2–9.4). In patients successfully bridged to liver transplantation, pre-treatment peripheral PD-1 profile was associated with advanced tumor staging (P < 0.005) with 2/4 of patients with elevations in PD-1 having T3-T4 TNM staging compared to 0 with low PD-1 expression.ConclusionLow lymphocyte count or elevated expression of the PD-1 checkpoint inhibitor is associated with incomplete response to LDT and increased risk of bridge-to-transplant tumor progression. Patients with impaired T cell homeostasis may benefit from PD-1 immunotherapy to improve response to LDT and improve bridge-to-transplant outcomes.

Targeting Endoglin Expressing Cells in the Tumor Microenvironment Does Not Inhibit Tumor Growth in a Pancreatic Cancer Mouse Model.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer and is known to have low immunogenicity and an immunosuppressive microenvironment. It is also characterized by high accumulation of dense stroma, composed of mostly cancer-associated fibroblasts (CAFs). Multiple subsets of CAFs are described, with one of them expressing the transforming growth factor (TGF)-β co-receptor endoglin. In previous work, we and others have shown that endoglin-expressing CAFs stimulate tumor progression and metastasis. Therefore, in this study, we set out to investigate the role of endoglin-expressing CAFs in pancreatic cancer progression.MethodsFirst, we investigated the expression of endoglin on CAFs in both human tissues as well as a mouse model for PDAC. Since CAF-specific endoglin expression was high, we targeted endoglin by using the endoglin neutralizing antibody TRC105 in the murine KPC model for PDAC.ResultsAlthough some signs of immune activation were observed, TRC105 did not affect tumor growth. Since 90% of the CD8+ T-cells expressed the immune checkpoint PD-1, we investigated the combination with a PD1 checkpoint inhibitor, which did not enhance therapeutic responses. Finally, genetic deletion of endoglin from collagen 1a1 expressing cells also did not affect the growth of the mouse KPC tumors.ConclusionOur results show that although endoglin is highly expressed on PDAC-CAFs and signaling is efficiently inhibited by TRC105, this does not result in decreased tumor growth in the KPC model for pancreatic cancer.

Single-cell polyfunctional proteomics of CD4 cells from patients with AML predicts responses to anti–PD-1–based therapy

AbstractAcute myeloid leukemia (AML) remains a difficult disease to treat disease. In a phase 2 clinical trial in patients with relapsed/refractory AML, combining the hypomethylating agent, azacitidine, with the PD-1 checkpoint inhibitor, nivolumab, demonstrated encouraging response rates (33%), median event-free, and overall survival, compared with a historical cohort of contemporary patients treated with azacitidine-based therapies, with an acceptable safety profile. Biomarkers of response are yet to be determined. In this study, we leveraged a multiplexed immune assay to assess the functional states of CD4+ and CD8+ cells at a single-cell level in pretherapy bone marrows in 16 patients with relapsed/refractory AML treated with azacitidine/nivolumab. Effector CD4+ but not CD8+ cells had distinct polyfunctional groups and were associated with responses and better outcomes. Further evaluation of the polyfunctional strength index composition across cell types revealed that interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) were the major drivers of enhanced polyfunctionality index of pretherapy CD4+ subset, whereas Granzyme B, IFN-γ, MIP-1b, and TNF-α drove the nonsignificantly enhanced pretreatment Polyfunctional Strength Index of CD8+ subset in the responders. Single-cell polyfunctional assays were predictive of response in AML and may have a potential role as a biomarker in the wider sphere of immunotherapy.

435P The AGITG Modulate study: Randomised phase II study testing manipulation of the tumour micro environment (TME) to enable synergy with PD1 inhibitors in microsatellite stable (MSS) metastatic colorectal cancer (mCRC)

PD-1 checkpoint inhibitors are active in microsatellite unstable (MSI) mCRC, which have an inflamed TME but are inactive in MSS-mCRC. The resistance of MSS mCRC is potentially related to the TME which excludes immune cells. The Modulate study tested 2 strategies designed to alter the TME in MSS mCRC, thereby enabling synergy with PD1 inhibitors.

CD27 expression on Treg cells limits immune responses against tumors

Regulatory T cells (Tregs) suppress immune responses and thus contribute to immune homeostasis. On the downside, Tregs also limit immune responses against tumors promoting the progression of cancer. Among the many mechanisms implied in Treg-mediated suppression, the inhibition of dendritic cells (DCs) has been shown to be central in peripheral tolerance induction as well as in cancers. We have shown previously that the maintenance of peripheral T cell tolerance critically depends on cognate interactions between Tregs and DCs and that the CTL priming by unsuppressed steady state DCs is mediated via CD70. Here, we have investigated whether the CD70/CD27 axis is also involved in Treg-mediated suppression of anti-tumor immunity. Using a mixed bone marrow chimeric mouse model in which we can deplete regulatory T cells in a temporally controlled fashion, we show that Treg-expressed CD27 prevents the breakdown of peripheral tolerance and limits anti-tumor immunity. Furthermore, ablation of Treg expressed CD27 acts synergistically with PD-1 checkpoint inhibition to improve CTL mediated immunity against a solid tumor. Our data thus identify Treg-expressed CD27 as a potential target in cancer immunotherapy.Key messagesTreg expressed CD27 maintains steady state DC tolerogenicTreg expressed CD27 limits anti-tumor immunityAblation of Treg expressed CD27 synergizes with PD-1 blockade to improve CTL mediated tumor control