anti-PD1 Antibody Research Articles

Nab-paclitaxel plus anti–PD-1 antibody as second-line treatment for advanced biliary tract cancer: An investigator-initiated phase 2 study (NapaSinti trial).

564 Background: Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. Gemcitabine + cisplatin ±durvalumab is the standard first-line treatment for advanced BTC. But in second-line setting, there is no satisfactory regimen for most patients without specific genetic mutations. This prospective, single-arm, phase 2 study is conducted to investigate the efficacy and safety of second-line nab-paclitaxel combined with sintilimab in advanced BTC patients. Methods: Eligible patients are histologically confirmed local advanced or metastatic adenocarcinoma or cholangiocellular carcinoma in biliary tract; aged from 18 to 75 years; with a performance status and adequate organ function; with documented disease progression after prior gemcitabine or fluorouracil-based systemic chemotherapy; not received taxol drugs or immune checkpoint inhibitors treatment. Enrolled patients will receive nab-paclitaxel 125mg/m2 on day 1, 8 plus sintilimab 200mg on day 1, administered intravenously every three weeks. The primary end point is objective response rate (ORR). The secondary end points are progression free survival (PFS), overall survival (OS) and adverse reactions. Next-generation sequencing (NGS) is voluntary before treatment. Results: Up to September 2022, 24 BTC patients have been enrolled, including 22 patients available for efficacy evaluation. The ORR is 27.3% (6/22), including 1 complete response (CR) and 5 partial response (PR). Disease control rate is 63.6% (14/22). And median PFS is 5.63 months (95% CI: 1.92-9.35 months). Median OS from enrollment to death of any cause is 12.60 months (95%CI: 7.84-17.36 months). The frequent grade 3 drug-related adverse events are leukopenia (16.7%), anemia (12.5%), neutropenia (8.3%), peripheral neuropathy (8.3%). There is no grade 4 drug-related adverse event occurred. One patient has experienced grade 3 immunological colitis. 11 participants have received NGS testing, with 9 ones are available for efficacy evaluation. Among the 9 participants, 5 patients harbor TP53 mutation [2 evaluated as PR, 2 SD (stable disease) and 1 PD (progressive disease)]; 3 patients harbor genetic mutations associated with DNA damage response pathway (2 evaluated as PR and 1 PD); and 1 patient is in status of microsatellite instability-high (MSI-H) evaluated as PR. Conclusions: The preliminary results of NapaSinti trial propose a brand new and effective regimen as second-line treatment for advanced biliary tract cancer. NGS may become a hopeful tool for efficacy prediction. Clinical trial information: ChiCTR2100052118 .

Trial in progress: Phase II study of niraparib and dostarlimab for the treatment of germline or somatic homologous recombination repair mutated metastatic pancreatic cancer.

TPS780 Background: Pancreatic adenocarcinoma is an aggressive malignancy with a limited number of therapeutic options. One subset of patients (up to 15%) carries germline and/or somatic mutations in homologous recombination repair genes, most notably BRCA1, BRCA2 and PALB2 amongst others, that confer sensitivity to PARP inhibition. Combinations of PARP inhibitors with anti-PD1 immunotherapy have shown activity in breast and ovarian cancer and have not yet been thoroughly studied in pancreatic cancer. Methods: We designed a single-arm phase 2 investigator-initiated study utilizing the combination of niraparib, a highly selective PARP inhibitor and a dostarlimab, an anti PD1 antibody, in the subset of pancreatic cancer patients with germline or somatic mutations in BRCA1/2, PALB2, BARD1, RAD51C, or RAD51D. Additional inclusion criteria include metastatic pancreatic adenocarcinoma, receipt of a platinum agent in 1st or 2nd line unless contraindicated, and at least 1 but not more than 2 prior lines of systemic therapy not including maintenance. Prior PARP inhibition is allowed, but not immediately prior to enrollment. Exclusion criteria include active unstable autoimmune disease or prior malignancy requiring active treatment within 2 years. Patients are treated with niraparib 200 mg orally once daily on days 1 through 21 of a 21 day cycle. Dostarlimab is administered IV 500 mg every 3 weeks for the 1st 4 cycles and then 1000 mg IV every 6 weeks subsequently. The primary endpoint of the study is the disease control rate at 12 weeks using standard iRECIST criteria. Twenty patients will be enrolled to ensure 19 evaluable. The design has 80% power to detected improvement in disease control rate from 25-50% with significance level of 0.10. Descriptive factors include gene mutated for inclusion, germline/somatic, and platinum refractoriness. Given the size of the study along with genetic heterogeneity there will be no interim analysis. Patients are being enrolled at 3 Mayo clinic sites in Rochester Minnesota, Phoenix Arizona, Jacksonville Florida. To date, 13 patients have been enrolled across all 3 sites. Full accrual is anticipated by early 2023. Correlative studies include genomic characterization of baseline tumors, assessment of immune infiltration of tumor microenvironment, tumor collection for organoid/xenograft, and serial circulating cell-free DNA and immune biomarkers. Trial Identifiers: NCT04493060, Mayo: MC1841. Supported by Glaxo Smith Kline. Clinical trial information: NCT04493060 .

Molecular characterization of metastatic colorectal cancer (mCRC) in patients (pts) treated with cetuximab and pembrolizumab.

178 Background: Anti-EGFR therapy has the potential to increase a localized anti-tumor immune response. We recently published the results of a phase Ib/II trial of the anti-EGFR antibody cetuximab in combination with the anti-PD1 antibody pembrolizumab in pts with advanced, RASwt CRC (PMID: 34645646). Despite its partial local immunologic efficacy, this combination of cetuximab and pembrolizumab was inactive. Here we present the results of comprehensive molecular characterization of pts with tumors amenable to DNA and RNA sequencing. Methods: Forty-two pts with RASwt mCRC were treated with cetuximab plus pembrolizumab. Archival or fresh tumor samples were obtained at baseline and, in select patients, on-treatment. Tumor samples underwent targeted DNA sequencing and whole transcriptome sequencing. Gene set enrichment analysis (GSEA), metabolic dysregulation assessment, and immune deconvolution were performed. Genomic data were linked to clinical outcomes. Results: Eighteen pts had tissue available for dual DNA/RNA extraction and sequencing. Of these, 10 had available matched on-treatment tumor samples. The most common mutations detected in protein coding regions were TP53 (14 pts), ERBB4 (5 pts), CDKN2A and APC (6 pts each). There were no statistically significant differences in progression-free survival (PFS) in pts with and without resistance-associated mutations (i.e., RAS, MET, ERBB4). Further, there was no significant difference associated with the consensus molecular subtype (CMS). However, when we compared patients with stable/increased tumor change percentage to those with decreased tumor change percentage, we found downstream transcriptional differences associated with altered metabolism, and in particular lipid and amino acid metabolism. Conclusions: We identified a significant number of patients with mutations predicting resistance to either or both cetuximab and pembrolizumab; however, none were associated with survival. However, we did identify metabolic pathways of interest, which may be associated with response to therapy. It is important to note, our analysis is limited by the small number of specimens (Trial registration NCT02713373). Clinical trial information: NCT02713373 .

Hyperpolarized 13C-Pyruvate to Assess Response to Anti-PD1 Immune Checkpoint Inhibition in YUMMER 1.7 Melanoma Xenografts.

There is currently no consensus to determine which advanced melanoma patients will benefit from immunotherapy, highlighting the critical need to identify early-response biomarkers to immune checkpoint inhibitors. The aim of this work was to evaluate in vivo metabolic spectroscopy using hyperpolarized (HP) 13C-pyruvate and 13C-glucose to assess early response to anti-PD1 therapy in the YUMMER1.7 syngeneic melanoma model. The xenografts showed a significant tumor growth delay when treated with two cycles of an anti-PD1 antibody compared to an isotype control antibody. 13C-MRS was performed in vivo after the injection of hyperpolarized 13C-pyruvate, at baseline and after one cycle of immunotherapy, to evaluate early dynamic changes in 13C-pyruvate-13C-lactate exchange. Furthermore, ex vivo 13C-MRS metabolic tracing experiments were performed after U-13C-glucose injection following one cycle of immunotherapy. A significant decrease in the ratio of HP 13C-lactate to 13C-pyruvate was observed in vivo in comparison with the isotype control group, while there was a lack of change in the levels of 13C lactate and 13C alanine issued from 13C glucose infusion, following ex vivo assessment on resected tumors. Thus, these results suggest that hyperpolarized 13C-pyruvate could be used to assess early response to immune checkpoint inhibitors in melanoma patients.

CD200+ cytotoxic T lymphocytes in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy.

Anti-PD-1/PD-L1 therapy, either by anti-PD-1 antibody or anti-PD-L1 antibody, has efficacy by reinvigorating tumor-infiltrating CD8+ T cells in a subset of patients with cancer, but it has unequal effects on heterogeneous CD8+ T cell populations. Hence, the subset crucial to efficacious PD-1 blockade therapy remains elusive. Here, we found an increase in tumor-infiltrating CD200+ cytotoxic T lymphocytes (CTLs) upon PD-1/PD-L1 blockade, with higher proportions of CD200+ T cells positively related to a favorable clinical outcome to anti-PD-1/PD-L1 therapy in three independent cohorts of patients with cancer. Using multiple mouse tumor models, we demonstrated that CD200+ CTLs are essential for efficacious anti-PD-L1 therapy. Mechanistically, we observed a unique chromatin landscape in CD200+ CTLs and found that these cells are enriched for tumor antigen-specific CTLs and have antitumor effector functions. Coinoculation of CD200+ CTLs with tumor cells led to robust tumor regression in two transplanted mouse models. Clinically, we found that infiltration of CD200+ CTLs into tumors could predict immunotherapy efficacy in six patient cohorts. Together, our findings reveal that CD200+ CTLs in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy and could serve as a predictor of successful immunotherapy in the clinic.

Abstract PR004: Older adult-specific microbes correlate with treatment response and markers of T-cell senescence in NSCLC

Abstract The gut microbiome changes with age and affects many aspects of human health, including response to cancer treatments. Cancer survival rates have improved with new treatment options, including immune checkpoint blockade (ICB); however, the objective response rate remains low. Manipulation of the microbiome is a promising approach to improving cancer outcomes, but the effect of age is understudied. Here, we sought to understand whether (1) specific microbes are associated with treatment response in older adults with non-small cell lung cancer (NSCLC) and (2) whether these microbes are the same as for younger adults. Next, we explored the causal effects of the microbiome on ICB response in mouse models and the relationship with blood-based markers of T-cell senescence. We conducted a prospective cohort study of adults ≥60 years with a new diagnosis of NSCLC who received any treatment modality. Stool was collected, and metagenomic whole-genome shotgun sequencing was performed. Blood T-cells were isolated, the RNA purified and then assessed for markers of senescence by nanostring. Response to treatment was determined by RECIST v1.1 criteria. Generalized linear regression was used to relate baseline microbiome abundances to treatment response and non-parametric correlations associated with CDKN2A (p16) expression to microbe abundances. To assess the causal role of the gut microbiome in ICB response, we gavaged gut microbiome samples from responders and non-responders into C57BL/6 mice to create human-microbiome avatar models. The mice were then injected with MC38 cancer cells and treated with anti-PD1 or isotype control antibodies, and tumor volume was measured over time. Biospecimens and best response data at three months were captured from 23 patients, of which five had a complete response, eight had a partial response, eight had stable disease, and two had progressive disease. Over 50 microbes were associated with a response after p-value adjustment. Responder stool was enriched for microbes associated with youth and ICB response (Bifidobacterium adolescentis, p = 2.64e-20). However, microbial taxa associated with response differed from those reported in younger populations (Firmicutes sp. CAG 145, p = 1.58e-20, Oscillibacter sp. 57-20, p = 7.96e-24). Stool from non-responders (NRs) was enriched in taxa previously linked to treatment-related toxicities and shorter progression-free survival (Streptococcus lutetiensis, p = 4.55E-24) but also contained microbes previously linked to response in younger adults (e.g., Roseburia sp. CAG 309, p = 5.16e-15). The T cell senescence marker, p16, correlated with the most enriched taxon in non-responders NRs (Streptococcus thermophilus, r = 0.45, p = 0.02), suggesting a connection between immune aging and the microbiome. Preliminary fecal transplant studies in mice showed improved ICB response in mice engrafted with stool from responders versus non-responders. Together, these data identify potential differences in the gut microbiomes of young and older adult NSCLC patients who respond to ICB. Citation Format: Daniel Spakowicz, Rebecca Hoyd, Caroline E. Wheeler, Nyelia Williams, Amna Bibi, Marium Husain, Srichandhana Rajamouli, Shankar Suman, Joseph Amann, Madison Grogan, Pooja Vibhakar, Dwight H. Owen, David P. Carbone, Ashley Rosko, Christin E. Burd, Carolyn J. Presley. Older adult-specific microbes correlate with treatment response and markers of T-cell senescence in NSCLC [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR004.

Anti-PD-1 antibodies recognizing the membrane-proximal region are PD-1 agonists that can down-regulate inflammatory diseases.

The PD-1 receptor triggers a negative immunoregulatory mechanism that prevents overactivation of immune cells and subsequent inflammatory diseases. Because of its biological significance, PD-1 has been a drug target for modulating immune responses. Immunoenhancing anti-PD-1 blocking antibodies have become a widely used cancer treatment; however, little is known about the required characteristics for anti-PD-1 antibodies to be capable of stimulating immunosuppressive activity. Here, we show that PD-1 agonists exist in the group of anti-PD-1 antibodies recognizing the membrane-proximal extracellular region in sharp contrast to the binding of the membrane-distal region by blocking antibodies. This trend was consistent in an analysis of 81 anti-human PD-1 monoclonal antibodies. Because PD-1 agonist antibodies trigger immunosuppressive signaling by cross-linking PD-1 molecules, Fc engineering to enhance FcγRIIB binding of PD-1 agonist antibodies notably improved human T cell inhibition. A PD-1 agonist antibody suppressed inflammation in murine disease models, indicating its clinical potential for treatment of various inflammatory disorders, including autoimmune diseases.

Radiotherapy plus camrelizumab affects peripheral CD8 T-cell differentiation subsets expressing PD-1, TIGIT, and CTLA-4 in esophageal squamous cell carcinoma.

Our previous phase Ib trial (NCT03222440) showed that radiotherapy plus the anti-PD-1 antibody camrelizumab is a safe and feasible first-line therapy for locally advanced esophageal squamous cell carcinoma. In this study, we divided peripheral CD8 T-cell differentiation subsets into 4 subpopulations (naive T cells, central memory T cells, effector memory T cells, and CD45RA+ effector memory T cells). We then investigated the influence of radiotherapy plus camrelizumab therapy on the proportions of the 4 subsets and their PD-1, TIGIT, and CTLA-4 expression as well as their proliferative activity and compared the effects with those of concurrent chemoradiotherapy. Nineteen and 15 patients with esophageal squamous cell carcinoma who received radiotherapy plus camrelizumab therapy and concurrent chemoradiotherapy, respectively, were enrolled in this study. We isolated peripheral blood mononuclear cells from these patients before treatment and longitudinally after the delivery of 40 Gy radiotherapy. Flow cytometry was conducted to detect peripheral CD8 T-cell subsets and PD-1, TIGIT, CTLA-4, and Ki67 expression levels in patients with esophageal squamous cell carcinoma. We found that radiotherapy plus camrelizumab therapy did not change the proportions of the 4 subsets or the expression of CTLA-4, but this therapy decreased PD-1 expression by the 4 subsets and TIGIT expression by effector memory T cells, as well as significantly enhanced the proliferative activity of CD8 T cells, whereas concurrent chemoradiotherapy produced different effects. In addition, we further identified peripheral biomarkers that potentially predict the outcome of radiotherapy plus camrelizumab therapy.

Sorting Transcriptomics Immune Information from Tumor Molecular Features Allows Prediction of Response to Anti-PD1 Therapy in Patients with Advanced Melanoma.

Immunotherapy based on anti-PD1 antibodies has improved the outcome of advanced melanoma. However, prediction of response to immunotherapy remains an unmet need in the field. Tumor PD-L1 expression, mutational burden, gene profiles and microbiome profiles have been proposed as potential markers but are not used in clinical practice. Probabilistic graphical models and classificatory algorithms were used to classify melanoma tumor samples from a TCGA cohort. A cohort of patients with advanced melanoma treated with PD-1 inhibitors was also analyzed. We established that gene expression data can be grouped in two different layers of information: immune and molecular. In the TCGA, the molecular classification provided information on processes such as epidermis development and keratinization, melanogenesis, and extracellular space and membrane. The immune layer classification was able to distinguish between responders and non-responders to immunotherapy in an independent series of patients with advanced melanoma treated with PD-1 inhibitors. We established that the immune information is independent than molecular features of the tumors in melanoma TCGA cohort, and an immune classification of these tumors was established. This immune classification was capable to determine what patients are going to respond to immunotherapy in a new cohort of patients with advanced melanoma treated with PD-1 inhibitors Therefore, this immune signature could be useful to the clinicians to identify those patients who will respond to immunotherapy.

Antitumor efficacy of multi-target in situ vaccinations with CpG oligodeoxynucleotides, anti-OX40, anti-PD1 antibodies, and aptamers.

To overcome immune tolerance to cancer, the immune system needs to be exposed to a multi-target action intervention. Here, we investigated the activating effect of CpG oligodeoxynucleotides (ODNs), mesyl phosphoramidate CpG ODNs, anti-OX40 antibodies, and OX40 RNA aptamers on major populations of immunocompetent cells ex vivo. Comparative analysis of the antitumor effects of in situ vaccination with CpG ODNs and anti-OX40 antibodies, as well as several other combinations, such as mesyl phosphoramidate CpG ODNs and OX40 RNA aptamers, was conducted. Antibodies against programmed death 1 (PD1) checkpoint inhibitors or their corresponding PD1 DNA aptamers were also added to vaccination regimens for analytical purposes. Four scenarios were considered: a weakly immunogenic Krebs-2 carcinoma grafted in CBA mice; a moderately immunogenic Lewis carcinoma grafted in C57Black/6 mice; and an immunogenic A20 B cell lymphoma or an Ehrlich carcinoma grafted in BALB/c mice. Adding anti-PD1 antibodies (CpG+αOX40+αPD1) to in situ vaccinations boosts the antitumor effect. When to be used instead of antibodies, aptamers also possess antitumor activity, although this effect was less pronounced. The strongest effect across all the tumors was observed in highly immunogenic A20 B cell lymphoma and Ehrlich carcinoma.

Evaluation of the antitumor activity of moronecidin (Piscidin)-like peptide in combination with anti-PD-1 antibody against melanoma tumor.

Immunotherapy has changed the landscape of oncology over the last decade and has become a standard of care for various cancers. Researchers previously demonstrated that B16-F10 melanoma in C57Bl6 mice is resistant to immune checkpoint inhibitors. The goal of this study was to investigate how anti-PD1 antibodies functioned in combination with a new antimicrobial peptide (AMP) called moronecidin-like peptide (MLP). We studied the cytotoxic effect of AMP on the B10-F16 tumor cell line with the MTT experiment. The necrotic and apoptotic cells were determined by Presidium iodide (PI) /Annexin V staining and flow cytometry-based methods. Mice were inoculated subcutaneously with B10-F16 tumor cells in the mammary gland. Each group was sacrificed two weeks after the last injection to examine tumor-specific CD8+ T cell responses using flow cytometry. Annexin V and PI staining assay revealed that MPL significantly induces apoptosis in B16F10 cells. It should be noted that MLP in combination with anti-PD-1 improved antigen-specific T-cell responses synergistically (P=0.01) when compared with respective monotherapy. Furthermore, when compared with the respective monotherapies, combination therapy significantly controlled tumor growth in B10-F16 tumor cells and increased survival rate. Treatments with anti-PD-1 inhibitors alone had only a minor effect on tumor size, whereas combination therapy resulted in significant tumor growth control and increased animal survival. MLP therapy combined with anti-PD-1 antibody improves anti-tumor immune response in addition to inducing tumor cell apoptosis. As a result, the evidence suggests that intratumoral injection of MPL can improve anti-PD-1 antibody antitumor response.

Isolated adrenocorticotropic hormone deficiency and sialadenitis associated with nivolumab: a case report

Immune checkpoint inhibition with anti-PD(L)1 and anti-CTLA4 antibodies has significantly changed cancer treatment during the last 10years. Nevertheless, boosting the immune system with immune checkpoint inhibition can result in immune-related adverse events, affecting different organ systems, among which the endocrine system is the most affected. However, there are few descriptions of the association of immune-related adverse events, and the pathophysiology of some is still lacking. Here, we report a 70-year-old Caucasian patient treated with nivolumab (anti-PD1 monoclonal antibody) after resection of a unique relapse of melanoma in the neck region who presented with sicca syndrome, extreme fatigue, and weight loss 6months after the start of anti-PD1 therapy. Blood tests revealed hypoglycemia and secondary hypocortisolism due to isolated adrenocorticotrophic hormone deficiency. Interestingly, brain methionine positron emission tomography/magnetic resonance revealed physiological metabolism of the pituitary gland, which was not increased in size, and no hypophyseal metastasis was detected. The sicca syndrome investigation revealed the absence of anti-SSA/SSB antibodies, while the labial salivary gland biopsy showed lymphoplasmatocytic infiltrates with a focus score of 1. To provide new insights into the physiopathology of the anti-PD1-related sialadenitis, we investigated the distribution of aquaporins 5 by immunostaining on the labial salivary gland acini, and compared this distribution with the one expressed in the primary Sjögren's syndrome. Contrary to patients with primary Sjögren's syndrome (in whom aquaporins 5 is mainly expressed at the basolateral side), but similar to the patients with no sialadenitis, we observed expression of aquaporins 5 at the apical pole. This new finding deserves to be confirmed in other patients with anti-PD1-related sialadenitis. Owing to these immune-related adverse events, anti-PD1 was stopped; nevertheless, the patient developed a new relapse 1year later (March 2020) in the neck region, which was treated by radiotherapy. Since then, no relapse of melanoma was seen (1.5years after radiotherapy), but the patient still requires hypophyseal replacement therapy. The sialoadenitis resolved partially. We report a combination of sialoadenitis and hypophysitis explaining extreme fatigue in a patient who was treated in the adjuvant setting with anti-PD1 for a melanoma relapse.

PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain

How PD-L1 expression is regulated in cancer is poorly understood. Here, we report that the ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in colorectal cancers (CRCs). ERBB3 is one of the four members of the EGF receptor family, all with protein tyrosine kinase domains. ERBB3 is a pseudokinase with a high binding affinity to ATP. We showed that ERBB3 ATP-binding inactivation mutant reduces tumorigenicity in genetically engineered mouse models and impairs xenograft tumor growth of CRC cell lines. The ERBB3 ATP-binding mutant cells dramatically reduce IFN-γ-induced PD-L1 expression. Mechanistically, ERBB3 regulates IFN-γ-induced PD-L1 expression through the IRS1-PI3K-PDK1-RSK-CREB signaling axis. CREB is the transcription factor that regulates PD-L1 gene expression in CRC cells. Knockin of a tumor-derived ERBB3 mutation located in the kinase domain sensitizes mouse colon cancers to anti-PD1 antibody therapy, suggesting that ERBB3 mutations could be predictive biomarkers for tumors amenable to immune checkpoint therapy.

Effect of M2-like macrophages of the injured-kidney cortex on kidney cancer progression

Chronic kidney disease (CKD) affects kidney cancer patients’ mortality. However, the underlying mechanism remains unknown. M2-like macrophages have pro-tumor functions, also exist in injured kidney, and promote kidney fibrosis. Thus, it is suspected that M2-like macrophages in injured kidney induce the pro-tumor microenvironment leading to kidney cancer progression. We found that M2-like macrophages present in the injured kidney promoted kidney cancer progression and induced resistance to anti-PD1 antibody through its pro-tumor function and inhibition of CD8+ T cell infiltration. RNA-seq revealed Slc7a11 was upregulated in M2-like macrophages. Inhibition of Slc7a11 with sulfasalazine inhibited the pro-tumor function of M2-like macrophages and synergized with anti-PD1 antibody. Moreover, SLC7A11-positive macrophages were associated with poor prognosis among kidney cancer patients. Collectively, this study dissects the characteristic microenvironment in the injured kidney that contributed to kidney cancer progression and anti-PD1 antibody resistance. This insight offers promising combination therapy with anti-PD1 antibody and macrophage targeted therapy.

Pembrolizumab in combination with gemcitabine for patients with HER2-negative advanced breast cancer: GEICAM/2015–04 (PANGEA-Breast) study

BackgroundWe evaluated a new chemoimmunotherapy combination based on the anti-PD1 monoclonal antibody pembrolizumab and the pyrimidine antimetabolite gemcitabine in HER2- advanced breast cancer (ABC) patients previously treated in the advanced setting, in order to explore a potential synergism that could eventually obtain long term benefit in these patients.MethodsHER2-negative ABC patients received 21-day cycles of pembrolizumab 200 mg (day 1) and gemcitabine (days 1 and 8). A run-in-phase (6 + 6 design) was planned with two dose levels (DL) of gemcitabine (1,250 mg/m2 [DL0]; 1,000 mg/m2 [DL1]) to determine the recommended phase II dose (RP2D). The primary objective was objective response rate (ORR). Tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumors and myeloid-derived suppressor cells (MDSCs) levels in peripheral blood were analyzed.ResultsFourteen patients were treated with DL0, resulting in RP2D. Thirty-six patients were evaluated during the first stage of Simon’s design. Recruitment was stopped as statistical assumptions were not met. The median age was 52; 21 (58%) patients had triple-negative disease, 28 (78%) visceral involvement, and 27 (75%) ≥ 2 metastatic locations. Progression disease was observed in 29 patients. ORR was 15% (95% CI, 5–32). Eight patients were treated ≥ 6 months before progression. Fourteen patients reported grade ≥ 3 treatment-related adverse events. Due to the small sample size, we did not find any clear association between immune tumor biomarkers and treatment efficacy that could identify a subgroup with higher probability of response or better survival. However, patients that experienced a clinical benefit showed decreased MDSCs levels in peripheral blood along the treatment.ConclusionPembrolizumab 200 mg and gemcitabine 1,250 mg/m2 were considered as RP2D. The objective of ORR was not met; however, 22% patients were on treatment for ≥ 6 months. ABC patients that could benefit of chemoimmunotherapy strategies must be carefully selected by robust and validated biomarkers. In our heavily pretreated population, TILs, PD-L1 expression and MDSCs levels could not identify a subgroup of patients for whom the combination of gemcitabine and pembrolizumab would induce long term benefit.Trial registrationClinicalTrials.gov and EudraCT (NCT03025880 and 2016–001,779-54, respectively). Registration dates: 20/01/2017 and 18/11/2016, respectively.

201P Phase II study of taminadenant (A2AR antagonist) + spartalizumab (anti PD-1 antibody) in patients with triple-negative breast cancer (TNBC)

Anti–PD-(L)1 agents have limited activity in relapsed/refractory (r/r) TNBC. Blockade of immune suppression by antagonism of the adenosine pathway may increase the antitumor activity of PD-1 inhibitors in r/r TNBC. Here, we present data on the A2AR antagonist TAM + the anti–PD-1 antibody spartalizumab in TNBC.

Efficacy of Anti-PD1 Blockade in Treating Recurrent or Metastatic Nasopharyngeal Cancer: A Systematic Review and Meta-analysis

ObjectivesAnti-PD1 antibody has emerged as a promising immunotherapeutic option in patients with recurrent and/or metastatic nasopharyngeal cancers (RM-NPC). We aim to summarise existing evidence on the use of anti-PD1 antibodies in the treatment of these patients and compare its effectiveness with standard-of-care palliative chemotherapy. Our secondary aim is to explore potential combination therapies with anti-PD1 antibodies. Materials and MethodsPubMed, Embase and Cochrane databases were systematically searched for studies comparing the efficacy of various anti-PD1 antibodies in the treatment of RM-NPC (either as first or second line treatment) from inception to 2 September 2022. Meta-analyses were performed to correlate the various anti-PD1 antibodies with primary endpoints including overall response rate disease control rate (DCR), progression free survival (PFS) and overall survival (OS). ResultsEighteen studies with 1,887 patients met the inclusion criteria. The use of anti-PD1 antibody monotherapy as second-line treatment of RM-NPC revealed an ORR of 23 % (95 % CI = 19 %-28 %) and DCR of 51 % (95 % CI = 42 %-60 %). The ORRs for first-line as well as a combination of first and second-line treatments were 21 % (95 % CI = 15 % − 30 %) and 22 % (95 % CI = 6 % − 56 %, I2 = 75 %) respectively. The 12-month PFS and 12-month OS was also 27 % (95 % CI = 21 %–33 %) and 63 % (95 % CI = 53 %-72 %) respectively. ORR was much higher at 73 % (95 % CI = 32 %-94 %) when anti-PD1 antibodies were combined with Gemcitabine plus Cisplatin. ConclusionAnti-PD1 antibody demonstrate considerable activity in previously treated RM-NPC patients. Combining anti-PD1 antibodies with gemcitabine and cisplatin chemotherapy enhanced the efficacy of treatment.

443 T-cell repertoire in metastatic melanoma patients developing skin leukoderma after treatment with checkpoint inhibitors

Development of skin leukoderma (LEU) is associated with a positive response to immunotherapy with checkpoint inhibitors in melanoma patients. Thus, we hypothesized that T cell hallmarks in patients who developed LEU could predict patient’s response to checkpoint inhibitors. To this extend, we analyzed T cells from peripheral blood of melanoma patients, classified as responders with LEU, responders without LEU, or no responders, throughout the treatment with anti-PD1 antibodies. We found that occurrence of LEU was associated with reduction of MAIT, Th17 and T-reg cell frequency in the blood.

447 Development of the combination therapy of anti-PD1 antibody with PAI-1 inhibitors in advanced melanoma patients

Plasminogen activating inhibitor-1 (PAI-1) is associated with poor clinical outcomes in cancer patients, and elevated levels of PAI-1 in both tissue and serum are correlated with poor response to therapy in various cancers, including skin cancer. PAI-1 is reported as a key regulator of PD-L1 expression on melanoma cells through endocytosis, leading to abrogating the efficacy of anti-PD1 antibodies (Abs). These findings suggested that PAI-1 expression might predict the efficacy of anti-PD1 Abs. From the above findings, at first, we evaluated the expression and production of PAI-1 in melanoma patients who treated with anti-PD1 Abs, and then, we investigated the immunomodulatory effects of PAI-1 on tumor-associated macrophages in vitro.

Protein kinase Cι mediates immunosuppression in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most prevalent form of non-small cell lung cancer (NSCLC) and a leading cause of cancer death. Immune checkpoint inhibitors (ICIs) of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling induce tumor regressions in a subset of LUAD, but many LUAD tumors exhibit resistance to ICI therapy. Here, we identified Prkci as a major determinant of response to ICI in a syngeneic mouse model of oncogenic mutant Kras/Trp53 loss (KP)-driven LUAD. Protein kinase Cι (PKCι)-dependent KP tumors exhibited resistance to anti-PD-1 antibody therapy (α-PD-1), whereas KP tumors in which Prkci was genetically deleted (KPI tumors) were highly responsive. Prkci-dependent resistance to α-PD-1 was characterized by enhanced infiltration of myeloid-derived suppressor cells (MDSCs) and decreased infiltration of CD8+ T cells in response to α-PD-1. Mechanistically, Prkci regulated YAP1-dependent expression of Cxcl5, which served to attract MDSCs to KP tumors. The PKCι inhibitor auranofin inhibited KP tumor growth and sensitized these tumors to α-PD-1, whereas expression of either Prkci or its downstream effector Cxcl5 in KPI tumors induced intratumoral infiltration of MDSCs and resistance to α-PD-1. PRKCI expression in tumors of patients with LUAD correlated with genomic signatures indicative of high YAP1-mediated transcription, elevated MDSC infiltration and low CD8+ T cell infiltration, and with elevated CXCL5/6 expression. Last, PKCι-YAP1 signaling was a biomarker associated with poor response to ICI in patients with LUAD. Our data indicate that immunosuppressive PKCι-YAP1-CXCL5 signaling is a key determinant of response to ICI, and pharmacologic inhibition of PKCι may improve therapeutic response to ICI in patients with LUAD.