PD-L1 Checkpoint Inhibitors Research Articles

Clinical outcomes of NSCLC patients experiencing early immune-related adverse events to PD-1/PD-L1 checkpoint inhibitors leading to treatment discontinuation.

The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood. The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported. The primary end points were median progression-free survival, overall survival, objective response rate, risk of progression of disease and risk of death. The correlation of clinic pathological features with early severe irAEs represented the secondary end point. Median PFS was 9.3 and 8.4months, median OS was 12.0months and 14.2months at a median follow-up of 18.1 and 22.6months in the LTD cohort and in the control cohort, respectively. The ORR was 40% (95% CI 17.2-78.8) in the LTD cohort and 32.7% (95% CI 27.8-38.2) in the control cohort. The risk of disease progression was higher in the LTD cohort (HR 2.52 [95% 1.10-5.78], P = .0288). We found no survival benefit in LTD cohort compared to the control cohort. However, early and severe irAEs might underly an immune anti-tumor activation. We identified a significant association with first-line immune checkpoints inhibitors treatment and good PS. Further studies on risk prediction and management of serious and early irAEs in NSCLC patients are needed.

Novel oncolytic adenovirus expressing enhanced cross-hybrid IgGA Fc PD-L1 inhibitor activates multiple immune effector populations leading to enhanced tumor killing in vitro, in vivo and with patient-derived tumor organoids

BackgroundDespite the success of immune checkpoint inhibitors against PD-L1 in the clinic, only a fraction of patients benefit from such therapy. A theoretical strategy to increase efficacy would be to...

Immunology and Immune Checkpoint Inhibition in Ovarian Cancer - Current Aspects.

In the last decade immunotherapies such as immune checkpoint blockade (ICB) against the PD-1/PD-L1 system have revolutionised the treatment of numerous entities. To date, ovarian cancer has benefited very little from this success story. Possible causes include a rather low mutational burden compared to other tumour types, inadequate presentation of (neo-)antigens, and increased infiltration with immunosuppressive immune cells such as regulatory T cells and tumour-associated macrophages. In the clinical trials completed to date, the response rates to PD-1/PD-L1 checkpoint inhibitors have therefore been disappointingly low as well, although isolated long-term remissions have also been observed in ovarian cancer. The task now is to find suitable predictive biomarkers as well as to identify combination partners for ICB therapy that can increase the immunogenicity of ovarian cancer or overcome immunosuppressive resistance mechanisms. This paper provides an overview of the immune milieu in ovarian cancer, its impact on the effect of ICB, and summarises the clinical trial data available to date on ICB in ovarian cancer.

Cancer-Associated Fibroblasts in Oral Cancer: A Current Perspective on Function and Potential for Therapeutic Targeting.

The role of the tumour microenvironement (TME) in cancer progression and resistance to therapies is now widely recognized. The most prominent non-immune cell type in the microenvironment of oral cancer (OSCC) is cancer-associated fibroblasts (CAF). Although CAF are a poorly characterised and heterogenous cell population, those with an “activated” myofibroblastic phenotype have been shown to support OSCC progression, promoting growth, invasion and numerous other “hallmarks of malignancy.” CAF also confer broad resistance to different types of therapy, including chemo/radiotherapy and EGFR inhibitors; consistent with this, CAF-rich OSCC are associated with poor prognosis. In recent years, much CAF research has focused on their immunological role in the tumour microenvironment, showing that CAF shield tumours from immune attack through multiple mechanisms, and particularly on their role in promoting resistance to anti-PD-1/PD-L1 checkpoint inhibitors, an exciting development for the treatment of recurrent/metastatic oral cancer, but which fails in most patients. This review summarises our current understanding of CAF subtypes and function in OSCC and discusses the potential for targeting these cells therapeutically.

Abstract 3137: Characterizing heterogeneity of CD8 inflammation in biopsied tumor tissues using novel image analysis techniques

Abstract Analyzing images of tissue sections stained with biomarker-specific indicators can generate quantitative, cell-specific expression data rather than relying on pathologist's ability to count cells and recapitulate confounding scoring paradigms. Beyond biomarker expression, numerous cell features can be measured such as the cell morphology, biomarker staining patterns and intensity, and localization of the cells within defined spatial compartments or relations to one another. One of the most studied immune cells in immuno-oncology (IO) is the cytotoxic T cell, whose biological function is to identify and destroy infected or dysfunctional cells; this function is complicated by numerous factors within the tumor microenvironment (TME). Tumor cells can aberrantly express immune checkpoint molecules designed to stop CD8 T cells from performing their tumor killing function. Additionally, CD8 T cell function may be perturbed by other immune modulating factors within the TME. IO drugs modulating tumor and immune cell interactions such as PD-L1 checkpoint inhibitors have shown that an inflammatory TME, represented by high CD8 presence in the tumors (inflamed tumors), is indicative of a better therapeutic response. Investigation of CD8 T cell status in biopsied tissues typically describes each tissue as one of three main phenotypes: Immune Desert, Immune Excluded, or Inflamed. Immune Desert tissues do not express appreciable levels of CD8 throughout the tissue. Immune Excluded tissues contain CD8, but the expression is almost exclusively localized to the stroma surrounding tumor nests. Inflamed tissues show higher percentages of CD8 within the tumor nests. While this phenotypic categorization is informative, CD8 expression is often calculated as a mean of expression through the tissue and does not take in to account the heterogeneous nature of tumor biology. This may result in a tumor containing one highly inflamed tumor nest being averaged out with multiple deserted tumor nests and a tissue categorized as excluded or deserted even though inflammation is present. To better represent the heterogeneity of inflammation within tumor tissues, we present an image analysis-based algorithm which not only separates out the tumor, stroma, and tumor/stroma margin, but identifies each tumor nest within the tissue as its own discrete object. This allows for the enumeration of number and size of all tumor nests within the tissue. Each tumor nest is given its own phenotypic classification (inflamed, excluded, or deserted) and the percentage of tumor nests displaying each phenotype. We demonstrate heterogeneity of inflammation assessment alongside standard mean phenotypic evaluations of CD8 expression in non-small cell lung cancer, bladder, and melanoma tumor samples. Practical use in clinical studies can help uncover response or resistance associated phenotypes related to tumor heterogeneity. Citation Format: Charles William Caldwell, Will Paces, Sofia Reitsma, Christopher Brueckner, Si T. Lee-Hoeflich, Roberto Gianani. Characterizing heterogeneity of CD8 inflammation in biopsied tumor tissues using novel image analysis techniques [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3137.

Abstract 1563: DRP-104, a broad acting glutamine antagonist, synergizes with immune checkpoint blockade in vivo

Abstract We previously reported that DRP-104, a novel broad acting glutamine antagonist, has significant therapeutic potential in cancer by directly targeting tumor metabolism and simultaneously inducing a potent antitumor immune response. We also reported the immunomodulatory effect of DRP-104 on tumor growth inhibition (TGI) as a single agent and in combination with PD-1/PD-L1 checkpoint inhibitors in the MC38 and CT26 colon cancer syngeneic models(1). DRP-104 mediated TGI is associated with increased tumor-infiltrating leukocytes (TIL) including T, NKT, and NK cells; M1-polarized tumor associated macrophages; and decreased immune-suppressive cells such as MDSCs.Here we further elucidate the immunomodulatory effect of DRP-104 on tumor growth inhibition. In the MC38 mouse model, CD8+, CD4+, or NK cells were depleted by anti-CD8+Ab, anti-CD4+Ab, or anti-asialoGM1 Ab respectively to assess the contribution of these immune cells towards DRP-104 efficacy. CD8+T cell depletion significantly reduced anti-tumor efficacy for DRP-104 (73.9% TGI in CD8+T depletion setting vs 120% TGI with 57.8% regression in undepleted animals). NK cell depletion delayed early anti-tumor response to DRP-104 treatment, while in undepleted mice DRP-104 treatment showed TGI as early as 2 days after dose initiation. Interestingly, CD4+depleted mice showed enhanced efficacy to DRP-104 with TGI of 213% (regressions) and 6/8 tumor free mice 29 days after the end of treatment vs 1/8 mice tumor free in the CD4+ undepleted group with DRP-104 treatment. As such, we tested the combination of DRP-104 with anti-TIGIT antibody which has been reported to deplete Treg cells in the TME(2). In MC38 (anti-TIGIT insensitive) and CT26 (anti-TIGIT sensitive), DRP-104 showed significant single agent TGI. Furthermore, combination of DRP-104 with anti-TIGIT Ab demonstrated enhanced tumor growth inhibition and resulted in improvement in survival. In summary, immune cell depletion experiments confirmed DRP-104's immuno-oncology mechanism of action. CD8+ or NK cell depletion reduced DRP-104 efficacy while CD4+ cell depletion enhanced efficacy. Furthermore, combination therapy of DRP-104 with anti-PD-1 or anti-TIGIT Ab achieved significantly enhanced anti-tumor efficacy even in checkpoint inhibitor resistant models. This unique and non-overlapping mechanism of action supports clinical development of DRP-104 alone and in combination with immune checkpoint inhibitors. The first in human clinical study of DRP-104 is ongoing.

PD-1/PD-L1 checkpoint inhibitors during late stages of life: an ad-hoc analysis from a large multicenter cohort

BackgroundThe favourable safety profile and the increasing confidence with immune checkpoint inhibitors (ICIs) might have boosted their prescription in frail patients with short life expectancies, who usually are not treated with standard chemotherapy.MethodsThe present analysis aims to describe clinicians’ attitudes towards ICIs administration during late stages of life within a multicenter cohort of advanced cancer patients treated with single agent PD-1/PD-L1 checkpoint inhibitors in Italy.ResultsOverall, 1149 patients with advanced cancer who received single agent PD-1/PD-L1 checkpoint inhibitors were screened. The final study population consisted of 567 deceased patients. 166 patients (29.3%) had received ICIs within 30 days of death; among them there was a significantly higher proportion of patients with ECOG-PS ≥ 2 (28.3% vs 11.5%, p < 0.0001) and with a higher burden of disease (69.3% vs 59.4%, p = 0.0266). In total, 35 patients (6.2%) started ICIs within 30 days of death; among them there was a higher proportion of patients with ECOG-PS ≥ 2 (45.7% vs 14.5%, p < 0.0001) and with a higher burden of disease (82.9% vs 60.9%, p = 0.0266). Primary tumors were significantly different across subgroups (p = 0.0172), with a higher prevalence of NSCLC patients (80% vs 60.9%) among those who started ICIs within 30 days of death. Lastly, 123 patients (21.7%) started ICIs within 3 months of death. Similarly, within this subgroup there was a higher proportion of patients with ECOG-PS ≥ 2 (29.3% vs 12.8%, p < 0.0001), with a higher burden of disease (74.0% vs 59.0%, p = 0.0025) and with NSCLC (74.0% vs 58.8%, p = 0.0236).ConclusionOur results confirmed a trend toward an increasing ICIs prescription in frail patients, during the late stages of life. Caution should be exercised when evaluating an ICI treatment for patients with a poor PS and a high burden of disease.

Pretreatment Eosinophil Counts in Patients With Advanced or Metastatic Urothelial Carcinoma Treated With Anti-PD-1/PD-L1 Checkpoint Inhibitors.

Eosinophils influence antitumor immunity and may predict response to treatment with immune checkpoint inhibitors (ICIs). To examine the association between blood eosinophil counts and outcomes in patients with advanced or metastatic urothelial carcinoma (mUC) treated with ICIs, we identified 2 ICI-treated cohorts: discovery (n=60) and validation (n=111). Chemotherapy cohorts were used as comparators (first-line platinum-based chemotherapy, n=75; second-line or more pemetrexed, n=77). The primary endpoint was overall survival (OS). Secondary endpoints were time on treatment (ToT) and progression-free survival. Univariate and multivariate analyses were performed using Cox proportional hazard models. Associations between changes in eosinophil count at weeks 2/3 and 6 after the start of ICI treatment were analyzed using landmark analyses. Baseline characteristics of the ICI cohorts were similar. In the discovery cohort, an optimal cutoff for pretreatment eosinophil count was determined [Eos-Lo: <100 cells/µL; n=9 (15%); Eos-Hi: ≥100 cells/µL; n=51 (85%)]. Eos-Lo was associated with inferior outcomes [OS: hazard ratio (HR), 3.98; 95% confidence interval (CI), 1.85-8.56; P<0.013; ToT: HR, 2.45; 95% CI, 1.17-5.10; P=0.017]. This was confirmed in the validation cohort [Eos-Lo: n=17 (15%); Eos-Hi: n=94 (85%)] (OS: HR, 2.51; 95% CI, 1.31-4.80; P=0.006; ToT: HR, 2.22; 95% CI, 1.2-3.80; P=0.004), and remained significant after adjustment for other prognostic factors. Changes in eosinophil counts at weeks 2/3 and 6 were not clearly associated with outcomes. In chemotherapy cohorts, eosinophil counts were not associated with outcomes. In conclusion, low pretreatment eosinophil count was associated with poorer outcomes in patients with mUC treated with ICIs, and may represent a new predictive biomarker.

Possible immunologic predictors of the PD-1/PD-L1 checkpoint inhibitors' efficiency in lung cancer patients.

e21035 Background: Immunotherapy with PD-1/PD-L1 check-point inhibitors (CPI) is a new trend in oncology. Their effect significantly depends on the patients` immune status. The aim of the study was to search the immunologic parameters of lung cancer (LC) patients receiving immunotherapy as factors that could predict their effect. Methods: 20 patients (12 male and 8 female) with LC had adenocarcinoma – 15 (75%), squamous cell carcinoma – 5 (25%). PD-1/PD-L1 CPI were used: 9 patients received atezolizumab (43%), 9 (43%) – pembrolizumab and 3 (14%) – nivolumab. The effect of therapy was evaluated according to imRECIST v.1.1. Factors of cell-mediated immunity were assessed by flow cytometry before treatment including immunotherapy. CD8+CD279+, CD4+CD279+, TLR2, TLR4, TLR3, TLR8 were studied. Results: Complete response was observed in 2 (9%) patients, partial response in 5 (24%), stabilization in 4 (19%) and progression in 8 (38%). In one patient the treatment was cancelled due to the development of immune-mediated complication (Guillain-Barre syndrome). The factors studied varied depending on different effect. In cases of LC stabilization/progression the initial amount of CD8+CD279+ cells were twice lower than in cases with complete/partial response. In the first group CD8+CD279+ cells` level before the treatment was 0,1-3,4%, while in the other group 4,1-9% (7,0±1,16%). In patients with stabilization/progression CD4+CD279+ cells` level before the immunotherapy was 0,1-3,3 and in patients with response to treatment 1,4-7,8% (3,4±0,8%) of total CD4+ lymphocytes. Besides, the LC patients with different effect of treatment had different initial amount of CD4+ Tem cells: stable response to CPI developed in patients with their higher levels (40,8±3,9%) vs 15,3±3,9% in cases of tumor progression (p &lt; 0.05). Initial high expression of TLR2 and TLR4 as well as low expression of TLR3 and TLR8 on monocytes in patients with response to immunotherapy suggests the contribution of innate immunity to its effect. Conclusions: Complete or partial response should be expected in cases of initially high per cent of T lymphocytes (CD4+, CD8+) CD4+ Tem cells and TLR2+, TLR4+ as well as low amount of TLR3+ and TLR8+ monocytes. These factors should be studied in future as predictive factors for effectiveness of CPI.

Identification of factors related to immunotherapy prognosis in patients with advanced head and neck squamous cell carcinoma.

e18003 Background: Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage and has a dismal prognosis. Anti-PD1/PD-L1 checkpoint inhibitors have shown survival benefit for the treatment on HNSCC, and are better tolerated than chemotherapy. Unfortunately, the response rate of immunotherapy is low for advanced HNSCC. Therefore, the identification of predictive biomarkers of response to anti-PD1/PD-L1 is a key point for better selecting patients that would benefit from immunotherapy. Methods: The present study included 44 patients with advanced HNSCC who received anti-PD-1 immunotherapy. Follow-up was available for them. Primary tumor tissues and matched blood samples were collected. Genome profiles were analyzed using a designed 543-gene panel based on NGS, and were available on 39 of 44 patients. Profiles of infiltrating immune cells were available for 44 patients. The infiltrating intensity of PD-1, PD-L1, CD8, CD68 and CD57 positive cells were assessed by multiplex immunohistochemistry. Results: The most frequently mutated genes were TP53 (79%), CDKN2A (33%), NOTCH1 (21%), CASP8 (13%) and PIK3CA (10%). Patients with mutations in the PI3K pathway showed a trend of longer OS (P = 0.06). Moreover, the TMB-high group showed significant superior OS than the TMB-low group (p = 0.0018). PD-L1 expression was positively correlated with CD8 expression within stroma, and PD-1 expression correlated significantly with PD-L1 and CD8 expression within both tumor and stroma areas. In addition, tumor/stromal PD-L1 and PD-1 expression were both associated with better OS (P &lt; 0.05). Prolonged OS was also observed in patients with more tumor and stromal infiltration of CD8+ cells, CD8+PD-L1+ cells, CD68+ macrophages, or nature killer (NK, CD57+) cells. Conclusions: Higher TMB, PD-L1 expression, as well as the infiltration of immune cells within both tumor and stromal area might serve as favorable prognostic markers in advanced HNSCC patients treated with anti-PD-1 immunotherapy.

Preliminary data from QUILT 3.055: A phase 2 multi-cohort study of N803 (IL-15 superagonist) in combination with checkpoint inhibitors (CPI).

2596 Background: There is currently a paucity of treatment options for checkpoint relapsed patients who have had an initial response but subsequently progress. N803, a novel IgG1 Fc-engineered IL-15-complexed protein may rescue checkpoint activity in a checkpoint independent manner via its selective enhancement of natural killer cell (NK) and CD8+ T cell number and function, without stimulation of T regs and MDSCs. Methods: QUILT 3.055, (NCT03228667) a phase 2b study of N803 plus investigator choice CPI in 11 tumor types: NSCLC, SCLC, Urothelial carcinoma, HNSCC, Merkel cell carcinoma, Melanoma (single PD-1/PD-L1 CPI or w/ ipilimumab), Renal cell carcinoma (RCC), Gastric cancer, Cervical cancer, Hepatocellular carcinoma, Microsatellite instability-high (MSI-H)/ mismatch repair deficient (dMMR) solid tumors, with a heterogeneous mix of prior therapies. We present interim data for 135 patients treated with CPI alone or in combination with chemotherapy as their most recent prior therapy. Trial inclusion required investigator assessed progression on last line of therapy, patients had either CR with relapse or partial response or stable disease for 6 months with progression as their most recent result of checkpoint therapy. Patients with hyperprogression or best initial response of progression were excluded. Subjects received N803 15mck/kg SC q 3 weeks in combination with the same checkpoint inhibitor on which they had their most recent progression. Results: Preliminary data from 135 patients (60% NSCLC) with treatment with checkpoint and N-803 following progression on the same checkpoint show CR 0%, PR 8%, Stable Disease 51%, Progression 29%, response unevaluable 12% to date. A PR or SD was seen in all subgroups. Median PFS 3.9 months (95% CI: 2.6,5.0). Median OS 13.8 months (95% CI: 11.8, 16.3) N-803 is well tolerated with grade 1-2 common N-803 treatment related adverse events (TRAE) were injection site reaction (68%), chills (32%) fatigue (26%), pyrexia (26%), flu-like illness (14%), nausea (12%) and no other individual AE &gt; 10%. Grade 3 N-803 TRAE were 12% but no individual grade 3 AEs were greater than 5%. Conclusions: N803 demonstrates low toxicity in patients previously treated with CPI and promising efficacy of cessation of progression and induction of response and durable stable disease in patients who had previously progressed on a CPI containing regimen in multiple tumor types and different CPIs. Clinical trial information: NCT03228667.

Vagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through excessive end organ inflammation. Despite improved understanding of the pathophysiology, management, and the great efforts worldwide to produce effective drugs, death rates of COVID-19 patients remain unacceptably high, and effective treatment is unfortunately lacking. Pharmacological strategies aimed at modulating inflammation in COVID-19 are being evaluated worldwide. Several drug therapies targeting this excessive inflammation, such as tocilizumab, an interleukin (IL)-6 inhibitor, corticosteroids, programmed cell death protein (PD)-1/PD-L1 checkpoint inhibition, cytokine-adsorption devices, and intravenous immunoglobulin have been identified as potentially useful and reliable approaches to counteract the cytokine storm. However, little attention is currently paid for non-drug therapeutic strategies targeting inflammatory and immunological processes that may be useful for reducing COVID-19-induced complications and improving patient outcome. Vagus nerve stimulation attenuates inflammation both in experimental models and preliminary data in human. Modulating the activity of cholinergic anti-inflammatory pathways (CAPs) described by the group of KJ Tracey has indeed become an important target of therapeutic research strategies for inflammatory diseases and sepsis. Non-invasive transcutaneous vagal nerve stimulation (t-VNS), as a non-pharmacological adjuvant, may help reduce the burden of COVID-19 and deserve to be investigated. VNS as an adjunct therapy in COVID-19 patients should be investigated in clinical trials. Two clinical trials on this topic are currently underway (NCT04382391 and NCT04368156). The results of these trials will be informative, but additional larger studies are needed.

Management of Thyrotoxicosis Induced by PD1 or PD-L1 Blockade

Context: Thyrotoxicosis is a common immune-related adverse event in patients treated with PD1 or PD-L1 checkpoint inhibitors. A detailed endocrinological assessment, including thyroid ultrasound and scintigraphy is missing, as are data on response to treatment and follow-up. Objectives: To better characterize the thyrotoxicosis secondary to immune checkpoint inhibitors, gaining insights into pathogenesis and informing management. Methods: We conducted a prospective cohort study of 20 consecutive patients who had normal thyroid function before starting immunotherapy and then experienced thyrotoxicosis upon PD1 or PD-L1 blockade. Clinical assessment was combined with thyroid ultrasound, scintigraphy, and longitudinal thyroid function tests. Results: Five patients had normal scintigraphic uptake (Sci+), no serum antibodies against the TSH receptor, and remained hyperthyroid throughout follow-up. The other 15 patients had no scintigraphic uptake (Sci-) and experienced destructive thyrotoxicosis followed by hypothyroidism (N= 9) or euthyroidism (N= 6). Hypothyroidism was more readily seen in those with normal thyroid volume than in those with goiter (P= 0.04). Among Sci- subjects, a larger thyroid volume was associated to a longer time to remission (P<0.05). Methimazole (MMI) was effective only in Sci+ subjects (P<0.05). Conclusions: Administration of PD1 or PD-L1 blocking antibodies may induce two different forms of thyrotoxicosis that appear similar in clinical severity at onset: a type 1 characterized by persistent hyperthyroidism that requires treatment with MMI, and a type 2 characterized by destructive and transient thyrotoxicosis that evolves to hypo- or eu-thyroidism. Thyroid scintigraphy and ultrasound help differentiating and managing these two forms of iatrogenic thyrotoxicosis

P78.09 Immunotherapy Beyond Progression for Patients with Advanced Non-Small Cell Lung Cancer

Immune checkpoint inhibitors (ICIs) have made a great breakthrough in the treatment of advanced non-small cell lung cancer (aNSCLC). However, whether immunotherapy beyond progression (IBP) is effective for aNSCLC still remains unknown. Therefore, we conducted a retrospective clinical study under real-world condition to investigate the efficacy of IBP for patients with aNSCLC and further identify the potential benefit subgroups patients. Chinese patients with aNSCLC who experienced progressive disease (PD) after receiving monotherapy or combination therapy based on PD-1/PD-L1 checkpoint inhibitors between January 2015 and March 2019 were screened in this study. Patients who were treated with ICIs exceeding 6 weeks after PD were defined as IBP, while those who received ICIs treatment less than 6 weeks after PD or discontinued subsequent ICIs therapy at the time of PD were defined as non-IBP. Clinical characteristics of patients were evaluated. Optimization-based method was applied to balance the clinical baseline characteristics between the two groups. Kaplan-Meier curves and log-rank test were used to analyze overall survival (OS) and progression-free survival (PFS). A total of 125 patients were included (IBP group, n=39; non-IBP group, n=86). Patients in IBP group had longer OS than that in non-IBP group (median OS, 26.6 vs 9.5 months; HR, 0.40; 95%CI, 0.23-0.69; P<0.001). The median PFS was 8.9 months in IBP group and 4.1 months in non-IBP group (HR, 0.41; 95% CI, 0.26-0.65, P<0.001). DCR was significantly higher in IBP group than in non-IBP group (89.7% vs 61.6%, P< 0.001). After balancing baseline covariates, the IBP group also showed longer PFS (median PFS: 9.7 vs 4.3 months, P<0.001) and OS (median OS: 26.6 vs 10.7 months, P=0.011). Similar results were also observed in both subgroups of initial immune monotherapy and combination therapy. Moreover, IBP therapy showed promising curative effects regardless of the patients’ response to prior line. Immunotherapy beyond progression is associated with longer overall and progression-free survival for patients with aNSCLC. Our findings may provide new options for the treatment of Chinese patients with aNSCLC who experienced disease progression after initial immunotherapy.

P78.15 Real-World Prognostic Model of Overall Survival in Patients With Advanced NSCLC Receiving Anti-PD1/PD-L1 as 2L Monotherapy

The objective of this retrospective, observational, non-interventional cohort study was to investigate prognostic factors of overall survival and build a model in patients with advanced non-small cell lung cancer (NSCLC) who received anti-PD1/PD-L1 immune checkpoint inhibitors (atezolizumab, nivolumab and pembrolizumab) as a single agent in second-line (2L) treatment. Patients with advanced NSCLC newly diagnosed between January 2011 and February 2020 who received atezolizumab, nivolumab or pembrolizumab as 2L monotherapy were included for analysis from the Flatiron Health electronic health record-derived de-identified database. Patients could not have received first-line treatment with clinical study drug(s) or anti-PD1/PD-L1 nor anti-CTLA4 immune checkpoint inhibitors. A Cox model with lasso regularization was used to build the prognostic model based on baseline clinical characteristics. The model was validated externally in 406 patients receiving 2L atezolizumab monotherapy from the OAK Phase III trial (NCT02008227). A total of 4224 patients were included with a median age of 69 years; 54% were male, 76% white, 67% had Stage IV at initial diagnosis and 69% had non-squamous histology. Top risk prognostic characteristics were ECOG performance status 2 and 3, older age, abnormal albumin and abnormally high calcium levels. Top protective prognostic characteristics were PD-L1 expression, extended time from advanced diagnosis to 2L treatment start date, abnormally high chloride levels, previous/current smoking history and abnormally low white blood cell count. The model was able to predict overall survival and showed a good performance in both the real-world cohort and the OAK trial (Figure). The prognostic model was able to predict overall survival in patients with advanced NSCLC receiving anti-PD1/PD-L1 immune checkpoint inhibitors as 2L monotherapy based on demographics and baseline clinical factors from a real-world setting.

Corrigendum: Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity

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A Multifunctional Nanovaccine based on L-Arginine-Loaded Black Mesoporous Titania: Ultrasound-Triggered Synergistic Cancer Sonodynamic Therapy/Gas Therapy/Immunotherapy with Remarkably Enhanced Efficacy.

In order to achieve better antitumor therapeutic efficacy and inhibit tumor metastasis, a multifunctional nanovaccine based on L-arginine (LA)-loaded black mesoporous titania (BMT) is fabricated. In this system, LA is utilized as the exogenous NO supplementation for gas therapy, and BMT is served as acoustic sensitizer for sonodynamic therapy. The ultrasound (US) as the exogenous stimulus can simultaneously trigger BMT and LA to produce singlet oxygen (1 O2 ) and NO gas at tumor sites, respectively. Interestingly, 1 O2 from US-excited BMT can promote the oxidation of LA to produce more NO. The high concentration of 1 O2 and NO in cancer cell can cause intracellular strong oxidative stress level and DNA double-strand breaks to induce cancer cell apoptosis ultimately. The US-triggered BMT@LA "nanovaccine" combining with immune checkpoint inhibitor PD-L1 antibody (αPD-L1) can induce strong antitumor immune response thus effectively killing primary tumors and further inhibiting metastatic tumors. Hence, BMT@LA-based "nanovaccine" combining with αPD-L1 checkpoint blockade treatment can realize synergetic sonodynamic/gas/immunotherapy with enhanced antitumor therapeutic effects.

MHC Class I Loss in Triple-negative Breast Cancer: A Potential Barrier to PD-1/PD-L1 Checkpoint Inhibitors.

Suppression of the immune system is intimately linked to the development and progression of malignancy, and immune modulating treatment options have shown promise in a variety of tumor types, including some triple-negative breast cancers (TNBC). The most dramatic therapeutic success has been seen with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand, PD-L1. Difficulty remains, however, in appropriate patient selection for treatment, as many PD-L1-positive cancers fail to show durable responses to PD-1/PD-L1 inhibition. Checkpoint inhibitor targeting of the adaptive immune response relies on the presence of major histocompatibility complex (MHC) class I molecules on the tumor cell surface for tumor antigen presentation. MHC class I loss has been previously described in breast cancer and represents a putative mechanism of immunotherapeutic resistance in this tumor type. One hundred seventeen invasive primary breast carcinomas with a range of histologic subtypes were evaluated on tissue microarrays containing formalin-fixed paraffin-embedded tissue. Loss of MHC class I expression was common among breast cancers, with greater than half of cases demonstrating either subclonal or diffuse loss. Fifty-nine percent of TNBC demonstrated loss of MHC class I, including 46% of those meeting the Food and Drug Administration-approved threshold of 1% for tumor-associated immune cell PD-L1 expression. MHC class I loss was particularly common in the apocrine subtype of TNBC (78%). MHC class I's employment as a predictive biomarker should be considered, as its loss may represent a barrier to successful enhancement of the antitumor adaptive immune response by PD-1/PD-L1 inhibition.

Determining Factors in the Therapeutic Success of Checkpoint Immunotherapies against PD-L1 in Breast Cancer: A Focus on Epithelial-Mesenchymal Transition Activation.

Breast cancer is the most common neoplasm diagnosed in women around the world. Checkpoint inhibitors, targeting the programmed death receptor-1 or ligand-1 (PD-1/PD-L1) axis, have dramatically changed the outcome of cancer treatment. These therapies have been recently considered as alternatives for treatment of breast cancers, in particular those with the triple-negative phenotype (TNBC). A further understanding of the regulatory mechanisms of PD-L1 expression is required to increase the benefit of PD-L1/PD-1 checkpoint immunotherapy in breast cancer patients. In this review, we will compile the most recent studies evaluating PD-1/PD-L1 checkpoint inhibitors in breast cancer. We review factors that determine the therapeutic success of PD-1/PD-L1 immunotherapies in this pathology. In particular, we focus on pathways that interconnect the epithelial-mesenchymal transition (EMT) with regulation of PD-L1 expression. We also discuss the relationship between cellular metabolic pathways and PD-L1 expression that are involved in the promotion of resistance in TNBC.

LncRNA HEIH/miR-939-5p interplay modulates triple-negative breast cancer progression through NOS2-induced nitric oxide production.

This study aimed to unravel the regulatory role of noncoding RNAs (ncRNA) on the nitric oxide (NO) machinery system in triple-negative breast cancer (TNBC) patients and to further assess the influence of NO-modulating ncRNAs on TNBC progression, immunogenic profile, and the tumor microenvironment (TME). The results revealed miR-939-5p and lncRNA HEIH as novel ncRNAs modulating NO machinery in TNBC. MiR-939-5p, an underexpressed microRNA (miRNA) in BC patients, showed an inhibitory effect on NOS2 and NOS3 transcript levels on TNBC cells. In contrast, HEIH was found to be markedly upregulated in TNBC patients and showed a modulatory role on miR-939-5p/NOS2/NO axis. Functionally, miR-939-5p was characterized as a tumor suppressor miRNA while HEIH was categorized as a novel oncogenic lncRNA in TNBC. Finally, knocking down of HEIH resulted in improvement of immunogenic profile of TNBC cells through inducing MICA/B and suppressing the immune checkpoint inhibitor PDL1. In the same context, knockdown of HEIH resulted in the alleviation of the immune-suppressive TME by repressing interleukin-10 and tumor necrosis factor-α levels. In conclusion, this study identifies miR-939-5p as a tumor suppressor miRNA while HEIH as an oncogenic lncRNA exhibiting its effect through miR-939-5p/NOS2/NO axis. Therefore, repressing BC hallmarks, improving TNBC immunogenic profile, and trimming TME.