Checkpoint Blockade In Solid Tumors Research Articles

Updates on the Importance of CD200:CD200R Checkpoint Blockade in Solid Tumors and B cell Malignancies

Updates on the Importance of CD200:CD200R Checkpoint Blockade in Solid Tumors and B cell Malignancies

ITK inhibition improves the response to immune checkpoint blockade in solid tumors

Abstract Cytotoxic CD8+ T cell (CTL) exhaustion is driven by persistent T cell receptor (TCR) stimulation in chronic infections and tumors. The exhausted state of T cells is characterized by impaired effector function and proliferative capacity, upregulation of multiple inhibitory receptors and altered transcriptional profiles. The phenotypic and epigenetic changes of these cells hinder effective antitumor immunity and immunotherapy. Therefore, reinvigorating exhausted T cells may provide significant clinical benefits to patients with cancer. Our approach is to reduce chronic TCR stimulation by inhibiting IL2-inducible T-cell kinase (ITK), a pivotal component of TCR signaling. In our study, we found that intermittent ITK inhibitor treatment significantly improved ICB response in three immune checkpoint blockade (ICB) -resistant solid tumors (melanoma, mesothelioma or pancreatic cancer) in vivo. In vitro, we demonstrated that specific ITK inhibitor and ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK) and ITK, directly reversed the exhaustion-related phenotypes in exhausted CTLs. The changes included enhanced cytokine production, decreased inhibitory receptor expression and changes in transcription factors. Subsequently, RNA-seq data revealed that exhaustion-related transcriptional profile of in vitro CTLs is reduced by ibrutinib treatment. Ibrutinib mediated reversal of CTL exhaustion was BTK independent. To conclude, our study demonstrates that ITK inhibition can be used to directly ameliorate CTLs exhaustion and overcomes immune checkpoint blockade resistance in solid tumors. This work was supported by the department of Immunology, KWF Grant 128371 (PDK), in part from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779295 (PDK), and by the China Scholarship Council for funding PhD fellowships (No. 201506160120 for MZ and 201906210055 for LL).

Focused ultrasound-mediated small-molecule delivery to potentiate immune checkpoint blockade in solid tumors.

In the last decade, immune checkpoint blockade (ICB) has revolutionized the standard of treatment for solid tumors. Despite success in several immunogenic tumor types evidenced by improved survival, ICB remains largely unresponsive, especially in "cold tumors" with poor lymphocyte infiltration. In addition, side effects such as immune-related adverse events (irAEs) are also obstacles for the clinical translation of ICB. Recent studies have shown that focused ultrasound (FUS), a non-invasive technology proven to be effective and safe for tumor treatment in clinical settings, could boost the therapeutic effect of ICB while alleviating the potential side effects. Most importantly, the application of FUS to ultrasound-sensitive small particles, such as microbubbles (MBs) or nanoparticles (NPs), allows for precise delivery and release of genetic materials, catalysts and chemotherapeutic agents to tumor sites, thus enhancing the anti-tumor effects of ICB while minimizing toxicity. In this review, we provide an updated overview of the progress made in recent years concerning ICB therapy assisted by FUS-controlled small-molecule delivery systems. We highlight the value of different FUS-augmented small-molecules delivery systems to ICB and describe the synergetic effects and underlying mechanisms of these combination strategies. Furthermore, we discuss the limitations of the current strategies and the possible ways that FUS-mediated small-molecule delivery systems could boost novel personalized ICB treatments for solid tumors.

Efficacy of dual checkpoint-blockade in solid tumors, part 1

Efficacy of dual checkpoint-blockade in solid tumors, part 1

Mammalian SWI/SNF Complex Genomic Alterations and Immune Checkpoint Blockade in Solid Tumors.

Prior data have variably implicated the inactivation of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) complex with increased tumor sensitivity to immune checkpoint inhibitors (ICI). Herein, we examined the association between mSWI/SNF variants and clinical outcomes to ICIs. We correlated somatic loss-of-function (LOF) variants in a predefined set of mSWI/SNF genes (ARID1A, ARID1B, SMARCA4, SMARCB1, PBRM1, and ARID2) with clinical outcomes in patients with cancer treated with systemic ICIs. We identified 676 patients from Dana-Farber Cancer Institute (DFCI, Boston, MA) and 848 patients from a publicly available database from Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY) who met the inclusion criteria. Multivariable analyses were conducted and adjusted for available baseline factors and tumor mutational burden. Median follow-up was 19.6 (17.6-22.0) months and 28.0 (25.0-29.0) months for the DFCI and MSKCC cohorts, respectively. Seven solid tumor subtypes were examined. In the DFCI cohort, LOF variants of mSWI/SNF did not predict improved overall survival (OS), time-to-treatment failure (TTF), or disease control rate. Only patients with renal cell carcinoma with mSWI/SNF LOF showed significantly improved OS and TTF with adjusted HRs (95% confidence interval) of 0.33 (0.16-0.7) and 0.49 (0.27-0.88), respectively, and this was mostly driven by PRBM1 In the MSKCC cohort, where only OS was captured, LOF mSWI/SNF did not correlate with improved outcomes across any tumor subtype. We did not find a consistent association between mSWI/SNF LOF variants and improved clinical outcomes to ICIs, suggesting that mSWI/SNF variants should not be considered as biomarkers of response to ICIs.

Radiosurgery and Immunotherapy in the Treatment of Brain Metastases

Radiation therapy represents a mainstay of treatment for patients with brain metastases. Recently, the widespread adoption of immune checkpoint blockade has led to keen interest in treating cancers with checkpoint inhibitors in place of, or as an adjunct to, traditional chemotherapy. However, with the exception of melanoma, immune checkpoint blockade in solid tumors has failed to achieve significant brain control in patients with brain metastases. The possibility of combining immune checkpoint blockade with radiation for the treatment of brain and other metastases represents an exciting new strategy that is in its early stages of investigation. Success with this combinatorial strategy has the potential to result in enhanced rates of brain control, less brain exposure to radiation, and improved cognitive outcomes. In this review, we discuss the mechanisms behind this synergy, describe its limitations, and suggest ways to move the field forward.

Abstract 4488: Effector B cells and tertiary lymphoid structures predict response to immune checkpoint blockade in solid tumors

Abstract Background: Cytotoxic T cell markers, PD-L1, and mutational burden have been identified as biomarkers of response to immune checkpoint blockade (ICB). However, there is a growing appreciation of B cells as biomarkers and mediators of response. We recently conducted a phase II trial of neoadjuvant ICB (NCT02519322) in patients with resectable melanoma, and found increased B cell infiltration in responders (R) versus non-responders (NR). Methods: We further investigated our B cell findings through whole transcriptomic profiling in samples with high tumor purity and also targeted immune profiling with deconvolution algorithm MCP counter. Spatial organization of the B cells was assessed with singlet and multiplex immunohistochemistry (IHC). Additionally, B cell phenotype was queried through mass cytometry. B cell gene expression signatures were validated in a cohort of renal cell carcinoma (RCC) patients (NCT02210117), and B cell phenotype in a metastatic melanoma cohort, both treated with ICB. Results: Whole transcriptomic analysis of the neoadjuvant melanoma ICB cohort identified that the most differentially expressed genes by response in baseline (b/l) samples were related to B cells and antibody production (MZB1, JCHAIN, IGLL5, FCRL5, p<0.0001). Targeted profiling via MCP counter confirmed higher B cells by response in all b/l and on-treatment (on-tx) samples (p=0.036 and p=0.038, respectively). This was verified by singlet CD20 IHC stains, which also showed that ICB increased B cells in R (p=0.004) but not NR. The B cells were present in organized tertiary lymphoid structures (TLS) in close proximity to T cells and follicular dendritic cells, and the ratio of area occupied by TLS was higher in R (p=0.037 b/l and 0.002 on-tx). These findings were validated in a RCC cohort, in which B cell lineage scores and TLS marker CXCL13 were higher in R at b/l (p=2.6e-03 and 3.3e-03, respectively). We then investigated the phenotype of the intratumoral B cells in the neoadjuvant melanoma cohort with mass cytometry. Within the tumor microenvironment, we identified naïve, class switched and unswitched memory B cell populations, and plasma cell-like populations (CD27+, IgD-, C38++, CD138-, CD20-). Higher frequencies of class switched memory B cell and plasma-like cell populations were observed in R, whereas NR were characterized by higher naïve B cells. Matching peripheral blood based CyTOF demonstrated non-overlapping clusters of B cell phenotypes. Single cell RNA sequencing in an independent cohort of metastatic melanoma patients also demonstrated class switched, activated B cells in addition to plasma cells, and that activation markers were significantly associated with response to ICB. Conclusion: Together, these data suggest that B cells, more specifically those with activated effector phenotypes, and TLS predict response to ICB and may also be contributing mechanistically to response. Citation Format: Sangeetha M. Reddy, Beth Helmink, Jianjun Gao, Shaojun Zhang, Keren Yizhak, Moshe Sade-Feldman, Rafet Basar, Jorge Blando, Guangchun Han, Vancheswaran Gopalakrishnan, Hao Zhao, Wenbin Liu, Hussein Tawbi, Rodabe Amaria, Michael Davies, Jeffrey Gershenwald, Elizabeth M. Burton, James Allison, Michael Tetzlaff, Katy Rezvani, Nir Hacohen, Padmanee Sharma, Linghua Wang, Jennifer Wargo. Effector B cells and tertiary lymphoid structures predict response to immune checkpoint blockade in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4488.

Abstract 4992: The occurrence of immune-related adverse events indicates better efficacy of immune checkpoint blockade in solid tumors: A systematic review and meta-analysis

Abstract Introduction: Immune-related adverse events (irAEs) were mostly induced by immune checkpoint blockade (ICB) and were associated with the immune response. Whether irAEs are associated with clinical benefits during ICB treatment in cancer patients remains unclear. This systematic review and meta-analysis aimed to investigate the relationship between irAEs and clinical efficacy. Methods: We systemically searched and selected irAEs and clinical outcome data from cancer patients treated with ICB in the PubMed, Embase, and Cochrane Central Trial databases up to July 26, 2018. Keywords used for the search included PD-1, PD-L1, CTLA-4, immune checkpoint and immune-related adverse events. The relationships between the occurrence of irAEs and the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were assessed using relative risk (RR) or hazard ratio (HR) values and 95% confidence intervals (CIs) in random-effect models. Results: Nineteen eligible observational articles were included in this systematic review and fourteen studies including 3022 participants (1264 with irAEs and 1758 with non-irAE) were included in our meta-analysis. The occurrence of irAEs was significantly associated with higher ORR (RR = 2.36, 95% CI: 1.85-3.02; P < 0.001), better PFS (HR = 0.48, 95% CI: 0.26-0.70; P < 0.001), and longer OS (HR = 0.42; 95% CI = 0.18-0.67; P = 0.001) than those in the non-irAE group. Subgroup analysis showed that the effect size of ORR in anti-PD-1 therapy (RR = 2.68, 95% CI, 2.21-3.26) was inferior to that of the anti-CTLA-4 therapy (RR = 1.91, 95% CI, 0.44-8.32). The meta-regression models also found that ICB type (anti-CTLA-4 or anti-PD-1) were associated with significant heterogeneity (P = 0.005). Conclusion: In conclusion, irAEs indicate greater ORR, PFS and OS than non-irAEs in ICB treatment, and the relationship in anti-PD-1 therapy was stronger than in anti-CTLA-4 therapy. With appropriate management of irAEs, the clinical predictor, continued treatment may be possible to maximize its potential ICB benefits. Note: This abstract was not presented at the meeting. Citation Format: Xu Yang, Dongxu Wang, Jianzhen Lin, Jianping Xiong, Junyu Long, Yi Bai, Jin Bian, Hanchun Huang, Xiaobo Yang, Yilei Mao, Xinting Sang, Haitao Zhao. The occurrence of immune-related adverse events indicates better efficacy of immune checkpoint blockade in solid tumors: A systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4992.

Abstract 2244: DeepIL-15 primed T cells synergize with PD-L1 blockade to overcome resistance to checkpoint immunotherapy

Abstract Introduction Interleukin-15 (IL-15) activates and expands both CD8+T cells and NK cells but not immunosuppressive Tregcells. While IL-15 is an attractive asset for cancer immunotherapy, its systemic administration is limited by toxicities. To limit IL-15 systemic exposure, we have developed DeepTM IL-15, a multimer of chemically crosslinked IL-15/IL-15 Rα/Fc heterodimers (IL15-Fc). Deep IL-15 is surface anchored to tumor reactive T cells prior to adoptive cell transfer (ACT). This novel therapeutic approach enables Deep IL-15 loading onto cells at concentrations unachievable with systemic IL15-Fc, causes autocrine T cell activation and expansion, yet limits systemic exposure and associated toxicities. The anti-tumor activity of T cell therapies has been limited by insufficient T cell expansion and by checkpoint immunosuppression. Here, we combined Deep IL-15 primed T cells with PD-L1 blockade to overcome these limitations. Methods Deep IL-15 was synthesized by incubation of IL15-Fc with a crosslinker. PMEL CD8+T cells (PMEL) were isolated from B6.Cg-Thy1a/Cy Tg(TcraTcrb)8Rest/J mice,activated, expanded, and Deep IL-15 was anchored to PMEL to generate Deep IL-15 Primed PMEL (Deep-15 PMEL). B16-F10 tumor-bearing mice were treated with cyclophosphamide (4 mg/mouse) one day prior to injection of 107Deep-15 PMEL (carrying ~ 58 ug of IL15-Fc)± anti-PD-L1 antibody (10 mg/kg q2w). We monitored mouse weight, tumor volumes, transferred and endogenous T cells, IL15-Fc systemic exposure, and cytokine release. Results Deep-15 PMEL showed significantly improved expansion and anti-tumor activity compared to PMEL, and provided long-term protection against tumor re-challenge. Importantly, the toxicity profile of Deep-15 PMEL was better than that of IL15-Fc co-injection with PMEL, yielding lower systemic exposure to IL15-Fc, less IFN-γinduction and no expansion of endogenous CD8+T and NK cells. Deep-15 PMEL resulted in 2/10 partial regressions and a statistically significant tumor growth inhibition compared to both vehicle and PD-L1 blockade alone. Co-administration of anti-PD-L1 further improved the anti-tumor activity of Deep-15 PMEL, resulting in 10/10 Complete Regressions (CR) and 6/10 Tumor Free Survivors. Conclusions By loading tumor-reactive T cells with Deep IL-15 before ACT, Torque's proprietary Deep Priming technology leverages the immune-stimulating power of IL-15 while avoiding immunotoxicity. Deep IL-15 Priming promotes engrafted T cell-specific activation and proliferation, and a favorable toxicity profile. In vivo transfer of Deep-15 PMEL combined with checkpoint inhibition was well tolerated and elicited remarkable anti-tumor activity in the PD-L1 refractory B16-F10 model, with 10/10 CRs. Torque is initiating a Phase I trial for TRQ15-01 (Deep IL-15 Primed multi-targeted human T cells) and planning a combination arm with checkpoint blockade in solid tumors. Citation Format: Elena Geretti, Xiaoyan Liang, Jesse Lyons, Philip Bardwell, Santina Caruso, Becker Hewes, Jonathan Fitzgerald, Karsten Sauer, Thomas Andresen. DeepIL-15 primed T cells synergize with PD-L1 blockade to overcome resistance to checkpoint immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2244.

DeepTM IL-15 Primed T cells Avoid Toxicity and Synergize with PD-L1 Blockade to Overcome Checkpoint Resistance in Cancer

Abstract Interleukin-15 (IL-15) is an attractive asset for cancer immunotherapy which activates and expands CD8+ T cells and NK cells but not immunosuppressive Treg cells. IL-15 can also promote protective T cell memory. However, IL-15 systemic administration is limited by toxicities, and IL-15 efficacy can be dampened by PD-1 checkpoint upregulation on T cells. To overcome IL-15 toxicities by focusing its activity on the tumor microenvironment, we have developed DeepTM IL-15, a multimer of crosslinked IL-15/IL-15 Rα/Fc heterodimers. In DeepTM IL-15 Primed T cells, DeepTM IL-15 is surface anchored to tumor reactive T cells prior to adoptive cell transfer (ACT) into tumor-bearing hosts. Here, we show that DeepTM IL-15 coating enables autocrine activation and expansion of the engrafted but not host T cells, protects mice from tumor re-challenge, and limits IL-15 systemic exposure and toxicities. We further show that PD-L1 blockade synergizes with DeepTM IL-15 coated T cell ACT to eradicate checkpoint-resistant tumors in mice. Based on these data, Torque is currently initiating a Phase I clinical study of TRQ15-01 (DeepTM IL-15 Primed multi-targeted human T cells) and planning a combination arm with checkpoint blockade in solid tumors.

Mechanism of Synergistic Effects on T Cell Activation By Avadomide (CC-122) and Nivolumab

Background: Avadomide (CC-122) is a cereblon modulator that promotes ubiquitination and degradation of the hematopoietic transcription factors Ikaros and Aiolos, leading to immunomodulation, such as T cell activation and increased interleukin-2 (IL-2) production in primary peripheral blood mononuclear cells (PBMCs). The immune checkpoint inhibitor nivolumab (nivo), an anti-PD-1 antibody, induces immune activation and can enhance immune response against various solid tumors. Previously, we have shown that the combination of avadomide and nivo synergistically enhance IL-2 production, T cell proliferation, and immune-mediated cytotoxicity, relative to single agent activity. To understand molecular mechanisms underlying these synergistic effects, we compared the effects of avadomide, nivo, or the combination on gene expression in primary human T cells using whole transcriptome RNA sequencing and differential pathway analysis.Methods: PBMCs were isolated from healthy donors (N=6), treated with DMSO/IgG, avadomide 50 nM, nivo 10 µg/mL, or avadomide and nivo for 1 hour, then stimulated with 0.5 ng/mL staphylococcus enterotoxin B for 48 hours. Culture supernatants were collected for cytokine analysis; T cells were isolated by magnetic cell separation for RNA extraction. RNA was sequenced by Illumina HiSeq v4; data was filtered to transcripts ≥10 counts across all samples and processed by DESeq2. Significantly differentially expressed genes (FDR-adj. P values <0.05) were computed for each treatment group relative to DMSO/IgG controls. Pathway analysis was performed with the GSEA Molecular Signatures Database (MSigDB) using the Hallmark and C2 curated gene sets, which comprise a diverse set of biological pathways, including KEGG and Reactome, to provide unbiased enrichment analysis. T cell-related pathways from the MSigDB C5 (Gene Ontology) collection were used to investigate specific effects on immune function. Synergy was defined by the fractional product method.Results: Avadomide, nivo, and the combination enhanced IL-2 production in SEB-stimulated PBMCs by 282%, 47%, and 586% respectively, compared with DMSO/IgG controls, confirming the synergistic effects on cytokine production. The top pathways upregulated in each treatment group included the following T cell related pathways: for avadomide - T cell receptor (TCR) signaling, JAK/STAT, cytokine/receptor interaction; for nivo - CD8 TCR pathway and HIF1A targets; and for the combination - TCR signaling, JAK/STAT, and HDAC3 targets which are required for T cell maturation and cytokine production. Combination treatment uniquely upregulated pathways including the Biocarta cytotoxic T cell pathway and calcium signaling in CD4+ T cells. Among the 7732 genes modified by any treatment, 1949 were uniquely differentially expressed by the combination. A targeted enrichment analysis using only T cell-related pathways from the C5 collection revealed that these uniquely differentially expressed genes represent processes such as T cell differentiation, proliferation, and activation.Conclusions: At the gene expression level, many T cell-related pathways were upregulated by one or more single agent and/or the combination. However, the presence of uniquely differentially regulated genes suggests that combination treatment induced broader effects in pathways involved in T cell differentiation, proliferation, and activation than either avadomide or nivo alone. Interestingly, the cytotoxic T cell pathway was uniquely upregulated by the combination, consistent with our previous finding of a significant increase in cytotoxicity with avadomide/nivo in combination. Calcium signaling in CD4+ T cell genes were also uniquely upregulated, suggesting that avadomide/nivo combination effects may involve nuclear factor of activated T cells (NFAT)-dependent T cell immune regulation. These data provide molecular support for the in vitro phenotypic activity of avadomide and checkpoint blockade on enhancing T cell activity. Avadomide is now under investigation in combination with checkpoint blockade in solid tumors (NCT02859324) and with CAR T therapy in lymphoma (NCT03310619). DisclosuresNakayama:Celgene Corporation: Employment, Equity Ownership. Stokes:Celgene Corporation: Employment, Equity Ownership. Waldman:Celgene Corporation: Employment, Equity Ownership. Hagner:Celgene Corporation: Employment, Equity Ownership. Gandhi:Celgene Corporation: Employment, Equity Ownership.

Abstract 4554: Assessment of the efficacy and safety of checkpoint inhibitors in the treatment of solid-tumor malignancies in a community cancer hospital

Abstract Introduction: High dose chemotherapy, radiation, and/or surgical resection have historically been the standard therapy for patients with progressive malignancies. However, promising studies have shown immunotherapy may improve overall survival and reduce tumor burden in advanced disease. Checkpoint inhibitors, such as PD-1 inhibitors pembrolizumab and nivolumab and PD-L1 inhibitor atezolizumab, are approved for use in several solid tumors, but the response to these agents has been limited. This study was designed to identify predictors for the therapeutic response to immunotherapy agents in a community cancer hospital. Procedures: A retrospective review using the electronic medical record system was done to identify 43 patients treated with immunotherapy at Avera Cancer Institute. The inclusion criteria included patients who had solid organ malignancies, received checkpoint inhibitor-based immunotherapy between May 31, 2014 and May 31, 2017, and completed next generation sequencing of tumor DNA. The exclusion criteria included patients who were less than eighteen years of age, pregnant, or received care in an outreach clinic when records were not available. Data obtained from the records included age, sex, diagnosis, treatment history, immunotherapy agent used, start and end date of immunotherapy agent, clinical outcome, pathology results, adverse reactions, and next generation sequencing results of tumor DNA. The collected data was assessed for patient characteristics and biomarkers that predicted responses to immune checkpoint blockade in solid tumors. Disease progression was assessed in correspondence with the response evaluation criteria in solid tumors guidelines. Results: A total of 43 patients were included, 14 male and 29 female. The median patient age was 66 years old. The main malignancies included were, breast (11 patients), lung (10 patients), and ovarian (7 patients). On average, the patients were treated with three previous lines of therapy before receiving immunotherapy treatment. The most common immunotherapy agent was pembrolizumab, with 28 of the patients receiving this, followed by 14 patients treated with nivolumab and one treated with atezolizumab. The median time patients on immunotherapy was 118 days. Patients with longer duration of immunotherapy, fewer previous treatment lines, and higher tumor mutational burden (TMB) had the best response to checkpoint inhibitors. Conclusions: The predictive biomarkers found in this study can be used to assist in patient selection for immunotherapy in the clinical setting, including TMB and the number of lines of previous therapy. Further studies will continue to find predictors of non-response and hyperprogressors. We hope to further evaluate patients who experienced a durable response to create new hypotheses about indicators of response. Citation Format: Rachel Elsey, Nathan Smith, April Lick, Lauren Metzger, Casey Williams, Brian Leyland-Jones, Ping Ye. Assessment of the efficacy and safety of checkpoint inhibitors in the treatment of solid-tumor malignancies in a community cancer hospital [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4554.

Prevalence of PDL1 Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors

Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors. To examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors. This retrospective study (October 1, 2012, to October 1, 2017) used a deidentified tumor database from a commercial company and annotated clinical records from a subset of patients treated at a university tertiary referral center. The study analyzed 118 187 tumors from the deidentified database, including a clinically annotated subgroup of 2039 malignant tumors. Comprehensive genomic profiling was performed on all samples to determine PDL1 amplification, microsatellite instability, and tumor mutational burden (TMB). A subset of patients was treated with PD-1/PD-L1 blockade. The prevalence of PDL1 amplification was determined among 118 187 patient samples that underwent next-generation sequencing. Solid tumors treated with checkpoint blockade were evaluated for response and progression-free survival (PFS). Of the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors. Most PDL1-amplified tumors (84.8%) had a low to intermediate TMB. PDL1 amplification did not always correlate with high-positive PD-L1 expression by immunohistochemical analysis. Six of 9 patients (66.7%) from 1 center with PDL1-amplified solid tumors had objective responses after checkpoint blockade administration. The median PFS among all treated patients was 15.2 months. Responders included 1 patient with glioblastoma (PFS, ≥5.2 months), 2 patients with head and neck squamous cell cancer (PFS, ≥9 and 15.2 months), 2 patients with metastatic basal cell cancer (PFS, 3.8 and ≥24.1 months), and 1 patient with urothelial cancer (PFS, ≥17.8 months). The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors. Additional large-scale, prospective studies of PDL1-amplified cancers are warranted to confirm the responses to checkpoint blockade described herein, even in the absence of microsatellite instability, high PD-L1 expression, and a high TMB.

Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes

The success of immunotherapy using immune checkpoint blockade in solid tumors and in relapsed/refractory classical Hodgkin lymphoma and chronic lymphocytic leukemia holds promise for targeted therapy in hematologic malignancies. Because efficacy of immunomodulatory therapy is correlated with numbers of cells that express programmed death (PD-1) ligands, we evaluated the expression of PD-L1 and PD-L2 proteins using immunohistochemistry in more than 702 diagnostic lymphoma biopsies. In classical Hodgkin lymphoma, PD-L1 and PD-L2 were expressed in 82% and 41% of cases, respectively, and PD-L1 but not PD-L2 expression correlated with Epstein-Barr virus in tumor cells. PD-L1 staining was detected in 80% of anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, and follicular dendritic cell sarcoma; 75% of nodular lymphocyte-predominant Hodgkin lymphoma; 53% of primary mediastinal large B-cell lymphoma; 39% of extranodal NK/T cell lymphoma; 26% of peripheral T-cell lymphoma; 10% of diffuse large B-cell lymphoma; and very rare examples of mantle, marginal zone, and small lymphocytic lymphomas. PD-L2 staining was present in 78% of primary mediastinal large B-cell lymphoma but in fewer cases in all other categories including 40% of follicular dendritic cell sarcoma and 7% of anaplastic large cell lymphoma. Our results confirm and extend prior studies of PD-L1 and provide new data of PD-L2 expression in lymphomas. The differential expression patterns in some tumor types and the expression of PD-L2 in the absence of PD-L1 raise the possibility of targeted therapy for additional subsets of patients with lymphoma.

Checkpoint blockade in solid tumors and B-cell malignancies, with special consideration of the role of CD200.

In the ontogeny of a normal immune response, a series of checkpoints must be overcome to ensure that unwanted and/or harmful self-directed activation responses are avoided. Many of the molecules now known to be active in this overseeing of the evolving immune activation cascade, contributing inhibitory signals to dampen an overexuberant response, belong to the immunoglobulin supergene family. These include members of the CD28/CTLA-4:B7.1/B7.2 receptor/ligand family, PD-1 and PDL-1, CD200 and CD200R, and the more recently described V-domain immunoglobulin suppressor of T-cell activation and its ligand (VSIG-3/IGSF11). Unfortunately, from the point of view of improving immunotargeting of cancer cells, triggering these checkpoint inhibitory signaling pathways, so necessary to maintain self-tolerance, simultaneously acts to prevent effective tumor immunity. The recent development of reagents, predominantly antibodies, to act as checkpoint blockade agents, has had a dramatic effect on human cancer treatment, with a marked reported success for anti-CTLA-4 and PD-1 in particular in clinical trials. This review provides a general overview of the data now available showing the promise of such treatments to our cancer armamentarium and elaborates in depth on the potential promise of what can be regarded as an underappreciated target molecule for checkpoint blockade in chronic lymphocytic leukemia and solid tumors, CD200.

Remarkable Responses to Checkpoint Blockade in Solid Tumors of Many Types

Mutations in genes that repair DNA damage are seen in >5% of common solid tumors. These “mismatch-repair” mutations are presumed to contribute to