Programmed Death-1 Checkpoint Blockade Research Articles

Antibiotic-dependent effect of probiotics in patients with non-small cell lung cancer treated with PD-1 checkpoint blockade

BackgroundWe previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications. Materials and methodsWe evaluated the prognostic ability of a “drug score” computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival. ResultsAmong the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53–0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52–0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54–0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54–0.69). ConclusionsAlthough we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted.

The Updated Status and Future Direction of Immunotherapy Targeting B7-H1/PD-1 in Osteosarcoma

Although the mortality rate of osteosarcoma (OS) patients has improved, there are still many unsolved problems concerning how to reduce recurrence and metastasis. In the tumor microenvironment, immune escape plays a more important role in tumor progression and development. Many costimulatory molecules of the B7 family have been reported to be involved in regulating immunological interactions between OS cells and immune cells. Among these molecules, B7-H1 and its receptor, programmed death-1 (PD-1), have been the focus of the fields of tumor immunology and have been recently applied in clinical trials of therapies for several solid tumors. These therapies, referred to as B7-H1/PD-1 checkpoint blockade therapies, are designed to block the interaction between the two molecules. Although the mechanism has been reported in some malignancies, the specific impact of B7-H1/PD-1 expression on OS has not been well defined. Here, we review the expression, function, and regulatory mechanism of the B7-H1/PD-1 axis in OS and introduce and compare the advantages and disadvantages of B7-H1/PD-1 immunotherapies in OS.

Cytocidal macrophages in symbiosis with CD4 and CD8 T cells cause acute diabetes following checkpoint blockade of PD-1 in NOD mice

Autoimmune diabetes is one of the complications resulting from checkpoint blockade immunotherapy in cancer patients, yet the underlying mechanisms for such an adverse effect are not well understood. Leveraging the diabetes-susceptible nonobese diabetic (NOD) mouse model, we phenocopy the diabetes progression induced by programmed death 1 (PD-1)/PD-L1 blockade and identify a cascade of highly interdependent cellular interactions involving diabetogenic CD4 and CD8 T cells and macrophages. We demonstrate that exhausted CD8 T cells are the major cells that respond to PD-1 blockade producing high levels of IFN-γ. Most importantly, the activated T cells lead to the recruitment of monocyte-derived macrophages that become highly activated when responding to IFN-γ. These macrophages acquire cytocidal activity against β-cells via nitric oxide and induce autoimmune diabetes. Collectively, the data in this study reveal a critical role of macrophages in the PD-1 blockade-induced diabetogenesis, providing new insights for the understanding of checkpoint blockade immunotherapy in cancer and infectious diseases.

Abstract LB-378: Regional delivery of clinical-grade mesothelin-targeted CAR T cells with cell-intrinsic PD-1 checkpoint blockade: Translation to a phase I trial

Abstract Background: We previously established the safety and antitumor efficacy of regionally delivered mesothelin-targeted M28z chimeric antigen receptor (CAR) T cells combined with programmed death-1 (PD-1) antibody (NCT02414269). As a next step, we developed next-generation CAR T cells equipped with a modified CD3z signaling domain with loss-of-function mutations within 2 of 3 ITAM motifs (1XX), and a PD-1 dominant negative receptor (PD1DNR) that provides T-cell intrinsic checkpoint blockade (M28z1XXPD1DNR CAR T cells). Herein, we provide evidence of the preclinical safety and enhanced antitumor efficacy of clinical-grade M28z1XXPD1DNR CAR T cells. Methods: Comparative cytotoxicity, proliferation, and cytokine secretion of human T cells engineered to express M28z or M28z1XXPD1DNR CAR were assessed by chromium-release, accumulation, and Luminex assays, respectively. The antitumor efficacy of a single dose (1x105 CAR T cells; E:T 1:1000) of intrapleurally administered M28z or M28z1XXPD1DNR CAR T cells was investigated in NSG mice with orthotopic pleural mesothelioma by serial bioluminescence imaging and by comparing survival. Following tumor eradication, functional persistence of CAR T cells was tested by repeated tumor challenge (increasing doses of 2x106 to 10x106 tumor cells). Results: In vitro, both M28z and M28z1XXPD1DNR CAR T cells exhibited antigen-specific cytotoxicity, accumulation, and effector cytokine secretion (table). In vivo, a single dose of M28z1XXPD1DNR CAR T cells led to tumor eradication, mice exhibited enhanced survival with weight gain, and resistance to tumor reestablishment upon 10 tumor rechallenges (table) versus a single dose of M28z CAR T cells. Table.In vitro and in vivo characteristics of M28z and M28z1XXPD1DNR CAR T-cell constructsM28zM28z1XXPD1DNRTargetMesothelinMesothelinCostimulatory domainCD28CD28CD3zNo mutations2 ITAM mutations (1XX)T-cell intrinsic checkpoint blockade (PD1DNR)NoYesIn vitro resultsHuman T-cell transduction, range25%-82%30%-89%PD-1 extracellular domain mRNA expression compared to untransduced, fold4158Cytotoxicity, rangeE:T 10:135%-45%25%-51%E:T 5:128%-44%20%-38%E:T 2:117%-32%14%-24%Accumulation, range, fold110-39053-622Effector cytokines (E:T 1:1, 24 h), rangeIL-214-23 ng/mL9-19 ng/mLTNF-α545-977 pg/mL380-852 pg/mLIFN-γ8-11 ng/mL6-15 ng/mLIn vivo resultsTumor eradication26 days19 daysMedian survival56 daysNot reachedTumor progression as measured by bioluminescence imaging following rechallengeRechallenged 3 times over 15 days+1 log+0.2 logsRechallenged 10 times over 52 days+3-4 logs+0.5 logsCurrent statusIn clinical trialIND submission pending Conclusion: Supported by the safety, tumor eradication, and functional persistence, M28z1XXPD1DNR CAR T cells will advance to IND submission and initiation of a phase I clinical trial in patients with pleural mesothelioma, and further extend our investigation to other mesothelin-expressing solid tumors. Citation Format: Stefan Kiesgen, Camille Linot, Hue T. Quach, Jasmeen Saini, Rebecca Bellis, Srijita Banerjee, Zhaohua Hou, Navin K. Chintala, Michel Sadelain, Prasad S. Adusumilli. Regional delivery of clinical-grade mesothelin-targeted CAR T cells with cell-intrinsic PD-1 checkpoint blockade: Translation to a phase I trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-378.

ICOS Is an Indicator of T-cell-Mediated Response to Cancer Immunotherapy.

Immunotherapy is innovating clinical cancer management. Nevertheless, only a small fraction of patient's benefit from current immunotherapies. To improve clinical management of cancer immunotherapy, it is critical to develop strategies for response monitoring and prediction. In this study, we describe inducible T-cell costimulator (ICOS) as a conserved mediator of immune response across multiple therapy strategies. ICOS expression was evaluated by flow cytometry, 89Zr-DFO-ICOS mAb PET/CT imaging was performed on Lewis lung cancer models treated with different immunotherapy strategies, and the change in tumor volume was used as a read-out for therapeutic response. ImmunoPET imaging of ICOS enabled sensitive and specific detection of activated T cells and early benchmarking of immune response. A STING (stimulator of interferon genes) agonist was identified as a promising therapeutic approach in this manner. The STING agonist generated significantly stronger immune responses as measured by ICOS ImmunoPET and delayed tumor growth compared with programmed death-1 checkpoint blockade. More importantly, ICOS ImmunoPET enabled early and robust prediction of therapeutic response across multiple treatment regimens. These data show that ICOS is an indicator of T-cell-mediated immune response and suggests ICOS ImmunoPET as a promising strategy for monitoring, comparing, and predicting immunotherapy success in cancer. SIGNIFICANCE: ICOS ImmunoPET is a promising strategy to noninvasively predict and monitor immunotherapy response.See related commentary by Choyke, p. 2975.

Molecular Profiling of Cohorts of Tumor Samples to Guide Clinical Development of Pembrolizumab as Monotherapy.

Molecular profiling of large databases of human tumor gene expression profiles offers novel opportunities for informing decisions in clinical development programs. Gene expression profile of programmed death ligand 1 (PD-L1) was explored in a dataset of 16,000 samples, including approximately 4,000 metastatic tumors, across >25 tumor types prevalent in the United States, looking for new indications for the programmed death 1 (PD-1) inhibitor pembrolizumab. PD-L1 expression was highly concordant with several genomic signatures indicative of immune-inflamed tumor microenvironment. Prevalence of activated immune-inflamed tumors across all tumor types was explored and used to rank tumor types for potential response to pembrolizumab monotherapy. The analysis yielded 3 tiers of indications in which high levels of PD-L1 and immune-inflamed signatures were found in up to 40% to 60%, 20% to 40%, and 0% to 20% of tumors. Tier 1 contained novel indications known at the time of analysis to be responsive to PD-1 checkpoint blockade in the clinic (such as melanoma and non-small cell lung cancer), as well as indications not studied in the clinic previously, including microsatellite instability-high colorectal, head and neck, bladder, and triple-negative breast cancers. Complementary analysis of an Asian/Pacific cancer dataset (gastric cancer) revealed high prevalence of immune-inflamed tumors in gastric cancer. These data contributed to prioritization of these indications for clinical development of pembrolizumab as monotherapy. Data highlight the value of molecular profiling in identifying populations with high unmet needs with potentially favorable response characteristics and accelerating development of novel therapies for these patients.See related commentary by Mansfield and Jen, p. 1443.

Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.

The immune system plays key roles in determining the fate of developing cancers by not only functioning as a tumour promoter facilitating cellular transformation, promoting tumour growth and sculpting tumour cell immunogenicity1–6, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion1,2,7. Yet clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer induced immunosuppression. In many individuals, immunosuppression is mediated by Cytotoxic T-Lymphocyte Associated Antigen-4 (CTLA-4) and Programmed Death-1 (PD-1), two immunomodulatory receptors expressed on T cells8,9. Monoclonal antibody (mAb) based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits—including durable responses—to patients with different malignancies10–13. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Herein, we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T cell rejection antigens following αPD-1 and/or αCTLA-4 therapy of mice bearing progressively growing sarcomas and show that therapeutic synthetic long peptide (SLP) vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Whereas, mutant tumour antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with αPD-1- and/or αCTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens (TSMA) are not only important targets of checkpoint blockade therapy but also can be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.