Concurrent PD-1 Research Articles

STRIvE-02 Arm C: Phase 1 study of concurrent PD-1 inhibition with B7-H3 CAR T cell immunotherapy for recurrent/refractory pediatric solid tumors.

e14626 Background: B7-H3 expression by a broad range of pediatric solid tumors has led to development of B7-H3-directed chimeric antigen receptor (B7-H3-CAR) T cells. However, early phase clinical trials of B7-H3-CAR T cells in recurrent/refractory solid tumors demonstrated inconsistent CAR T cell expansion and limited anti-tumor activity. We subsequently developed a dual transduced CAR product expressing B7-H3-CAR and CD19-CAR (CARB7H3x19) to enhance CAR T cell expansion with antigenic stimulation by normal B cells (STRIvE-02 Arm B). Augmented expansion was observed but CAR T cell persistence was variable, leading to a hypothesis that concurrent use of pembrolizumab (pembro), a PD1-inhibitor, would help prolong persistence, leading to improved anti-tumor activity. Methods: Patients up to age 26 years with recurrent/refractory solid tumors (excluding primary CNS) enrolled onto Arm C of STRIvE-02 to examine safety and feasibility of CARB7H3x19 at a dose of 0.5 x 106 CD19-CAR T/kg followed by pembro 2 mg/kg (max 200 mg) either 7- (Dose regimen (DR) 1) or 21-days (DR 2) post-CAR T cell using a 3+3 statistical design. All subjects received lymphodepletion with fludarabine and cyclophosphamide prior to CAR T cells. CTCAEv5 was used for toxicity grading. Results: Of six patients (pts) enrolled (age range 11–25 yrs, median 20 yrs, four received CAR T cell+pembro; three received DR1 pembro (day (D)+7), and one received DR2 (D+21). A pt on DR2 with nonseminomatous germ cell tumor developed grade (gr) 5 immune effector cell-associated hyperinflammatory syndrome (IEC-HS) on D+17 prior to pembro, resulting in trial suspension. One pt did not receive CAR T cells and is unevaluable. Adverse effects occurring in pts who received pembro included gr 3 fever in setting of neutropenia (n=1), and gr 2 hyperthyroidism (n=1), with no dose limiting toxicity attributed to CAR T cell+pembro. Maximum circulating CAR T expansion for Arm C was 192.18 cells/uL (range 6.86 – 192.18 cells/uL) with median persistence of 28 days (range 28 - 84), compared to a maximum circulating CAR T expansion of 740.95 cells/uL (range 8.29 – 740.95 cells/uL) and median persistence of 65 days (range 21 - 274) in pts treated on Arm B receiving the same CAR dose level (n=8). D+28 disease restaging in the four Arm C pts who received CAR T cells+pembro demonstrated stable disease (n=1) and disease progression (n=3). Conclusions: Although we observed tolerable toxicity among patients who received CAR T cell+pembro, the small number of patients limit full toxicity assessment. T cell expansion and persistence was observed, but the effects of pembro on CAR T cell fitness are unclear. Phenotypic characterization of circulating CAR T cells is underway to further assess impact of pembro. Of note, this is the first reported death attributed to IEC-HS in a patient after receiving B7-H3-CAR T cells. Investigations into etiology are ongoing. Clinical trial information: NCT04483778 .

A Novel Translational PET Imaging Approach to Quantifying Distal Tumor Immune Activation After Targeted Radiation Therapy and Checkpoint Blockade

ObjectivesThis study aimed to provide a novel non-invasive method to quantify abscopal immune activation and predict combinational treatment response using [68Ga]-NOTA-GZP PET imaging. Materials/Methods4T1 breast cancer cells were implanted bilaterally in the mammary fat pad of Balb/c mice and Lewis's lung cancer cells (LLC) were implanted bilaterally on the shoulders of C57/Bl6 mice. One of the tumors received a single fraction of 12Gy irradiation followed by combination of concurrent PD-1 and CTLA-4 inhibitors or controls. Tumor growth of the irradiated and non-irradiated tumors was measured and compared to 12Gy irradiation only, checkpoint inhibitor only, and no treatment control group. Changes in granzyme B activity were assessed with [68Ga]-NOTA-GZP PET imaging from baseline and every three days until day 9. ResultsIn the 4T1 model, concurrent treatment with dual checkpoint inhibitors (CPI) and radiation resulted in reduction of the irradiated tumor volume at day 30. At this same time point, the non-irradiated tumor volume for combination treatment decreased significantly, consistent with abscopal immune activation. Similarly, in the LLC model, concurrent treatment inhibited tumor growth on the non-irradiated tumor at day 15. Importantly, on day 9, granzyme B PET signal in both 4T1 and LLC models was significantly higher in the non-irradiated tumors that responded to concurrent treatment compared to subsequent non-responding tumors. A similar lack of granzyme B signal was observed in the non-irradiated tumors from mice that received radiation or CPI only and control tumors. ROC analysis identified a PET threshold of 1.505 and 1.233 on day 9 that predicted treatment response in 4T1 and LLC models, respectively. Conclusion[68Ga]-NOTA-GZP PET imaging was able to non-invasively predict abscopal immune activation prior to subsequent tumor volume changes after combination treatment. It provides a potential translational paradigm for investigating distal immune activation post-radiation in a clinical setting.

Impact of nab-paclitaxel plus PD-1/PD-L1 inhibitor on chemorefractory relapsed small-cell lung cancer.

Background: The present study evaluated the efficacy and safety of nab-paclitaxel (nab-PTX) with a concurrent PD-1/PD-L1 inhibitor in patients with refractory relapsed small-cell lung cancer (SCLC). Patients & methods: We retrospectively analyzed 240 patients with refractory relapsed SCLC: 40 patients were treated with nab-PTX plus PD-1/PD-L1 inhibitor, and 200 received traditional chemotherapy. Results: Median progression-free survival in the nab-PTX plus PD-1/PD-L1 inhibitor and traditional chemotherapy groups was 3.6 and 2.5months (p=0.0021), respectively. The median overall survival was 8.0 and 5.2months (p=0.0002), respectively. No new safety issues were identified. Conclusion: Nab-PTX plus PD-1/PD-L1 inhibitor significantly improved survival in patients with refractory relapsed SCLC compared with traditional chemotherapy.

Intratumoral co-injection of the poly I:C-derivative BO-112 and a STING agonist synergize to achieve local and distant anti-tumor efficacy

BackgroundBO-112 is a nanoplexed form of polyinosinic:polycytidylic acid that acting on toll-like receptor 3 (TLR3), melanoma differentiation-associated protein 5 (MDA5) and protein kinase RNA-activated (PKR) elicits rejection of directly injected...

Abstract 1586: Oncolytic virus HSV-1/ICP34.5-/ICP47-/mFLT3L/mIL12 promotes systemic anti-tumor responses and cooperates with immuno-modulatory agents in multiple mouse syngeneic tumor models

Abstract Oncolytic virotherapy is an emerging treatment modality that may hold promise as a therapeutic option for cancer patients who do not respond to checkpoint inhibitors. Oncolytic viruses preferentially replicate in tumor cells, offer the ability to express transgenes and have been shown to modify the local and distant tumor microenvironments from immunosuppressive to immunostimulatory. We generated HSV-1/ICP34.5-/ICP47-/mFLT3L/mIL12, an oncolytic virus based on a modified herpes simplex virus type 1 (HSV-1) designed to selectively replicate in tumors and produce murine FMS-like tyrosine kinase 3 ligand (mFLT3L) to enhance dendritic cell expansion and T cell priming, and murine interleukin-12 (mIL12) to potentiate type I helper and cytotoxic T cell responses. We confirmed the expression and bioactivity of mFLT3L and mIL12 in vitro and evaluated the efficacy of HSV-1/ICP34.5-/ICP47-/mFLT3L/mIL12 alone and in combination with anti-PD-1 or anti-4-1BB treatment in multiple syngeneic mouse tumor models. Bilateral tumor models were used and only one tumor was treated via intratumoral injection with HSV-1/ICP34.5-/ICP47-/mFLT3L/mIL12. Anti-tumor responses were evaluated in the injected tumor (local response), the uninjected tumor (abscopal) and via splenic immune profiling (systemic). HSV-1/ICP34.5-/ICP47-/mFLT3L/mIL12 treatment alone led to tumor growth inhibition in both treated and contralateral tumors, and a significant increase in overall survival in the A20, Neuro2a and MC38 models. HSV-1/ICP34.5-/ICP47-/mFLT3L/mIL12 in combination with anti-PD-1 blocking antibody further improved tumor growth inhibition in both treated and contralateral tumors in the MC38 syngeneic model, and significantly increased median overall survival compared to either agent as a monotherapy. In addition, HSV-1/ICP34.5-/ICP47-/mFLT3L/mIL12 in combination with an agonistic antibody targeting 4-1BB significantly increased overall survival compared to either agent as a monotherapy in the MC38 model. To understand antigen-specific anti-tumor T cell responses, MC38 tumor antigen epitopes were identified by combining exome sequencing and MHC/HLA-binding prediction algorithms. Antigen-specific T cell responses were measured in an IFN-γ ELISPOT assay using splenocytes from treated mice. HSV-1/ICP34.5-/ICP47-/mFLT3L/mIL12 induced and/or enhanced systemic T cell responses directed against both tumor neoantigens and tumor-associated antigens. Together, these data reveal that treatment with HSV-1/ICP34.5-/ICP47-/mFLT3L/mIL12 can cause direct tumor lysis and induce an adaptive, systemic T cell-mediated anti-tumor immune response that can be further enhanced by concurrent PD-1 blockade or 4-1BB agonism in multiple syngeneic mouse tumor models. Citation Format: Keegan Cooke, Walter H. Meisen, Petia Mitchell, Juan Estrada, Jinghui Zhan, Jessica Orf, Peng Li, Christina de Zafra, Jing Qing, Jason DeVoss. Oncolytic virus HSV-1/ICP34.5-/ICP47-/mFLT3L/mIL12 promotes systemic anti-tumor responses and cooperates with immuno-modulatory agents in multiple mouse syngeneic tumor models [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 1586.

Molecular Pathways Responsible for Adaptive Resistance to Single-Checkpoint Inhibition May Reveal Biomarkers and Immunotherapy Targets in Multiple Myeloma Patients

Immune checkpoints blocking antibodies represent a promising strategy to harness anti-tumor immune responses and improve the clinical outcome of patients with hematological malignancies. Early studies based on single-agent PD-1 blockade have fallen short of clinical expectations in multiple myeloma patients. Thus, several strategies are under consideration to implement and optimize the clinical efficacy of immune checkpoint blockade in multiple myeloma patients. We have focused on Vγ9Vδ2 T cells because we believe that these cells are very sensitive tools to assess the immune competence of multiple myeloma (MM) patients in the tumor microenvironment. By interrogating the bone marrow (BM) Vγ9Vδ2 T-cell immune reactivity to phosphoantigens, we have revealed a very early and unexpected tumor microenvironment commitment to immune suppression which is already detectable in monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted in clinical remission after autologous stem cell transplantation. Multiple cell subsets (myeloma cells, myeloid-derived suppressor cells, regulatory T cells, bone marrow stromal cells) are involved in Vγ9Vδ2 T-cell inhibition via several immune suppressive mechanisms including the immune checkpoint circuity.We have shown that there is a multifaceted immune checkpoint expression in the tumor microenvironment which is dependent on the clinical stage and cannot be neutralized with single-agent PD-1 blockade. To test our hypothesis that adaptive resistance to PD-1 blockade in MM patients may be due to the compensatory up-regulation of other immune checkpoints, we analyzed the expression of other inhibitory receptors (TIM-3, LAG-3, TIGIT and CTLA-4) in PB and BM Vg9Vd2 T cells from healthy donors and MM patients and observed that also TIM-3 beyond PD-1 is significantly upregulated in BM Vγ9Vδ2 T cells from MM patients at diagnosis. Unlike healthy immune cells, the attempt to activate functionally exhausted immune cells can further compromise their anti-tumor functions. pAg stimulation of PD-1+ and TIM-3+ BM Vγ9Vδ2 T cells further increases their inhibitory receptor expression. Interestingly, TIM-3 up-regulation is even more pronounced than PD-1 up-regulation in BM Vγ9Vδ2 T cells and it is specular to Vγ9Vδ2 T -cell proliferation, confirming that any inappropriate attempt to activate these cells leads further worsen their immune competence status. Our observations about the compensatory up-regulation of multiple inhibitory receptors (PD-1 and TIM-3) on BM Vγ9Vδ2 T cells and the further up-regulation of TIM-3 after anti-PD1 treatment suggested us to assess the combination of both immune checkpoint inhibitors (anti-PD1 and anti-TIM3) to overcome the PD-1 single blocking resistance and recover anti-myeloma reactivity. TIM-3 blockade alone was able to partially recover pAg-induced Vγ9Vδ2 T-cell proliferation but the best recovery was obtained when pAg stimulation is carried out in the presence of concurrent PD-1 and TIM-3 blockade. To investigate the molecular mechanisms behind the up-regulation of multiple immune checkpoints responsible for PD-1-mediated hyporesponsiveness and the effector cells exhaustion, we analyzed the main PD-1-mediated (PI3K/AKT) and TIM-3-mediated (JAK/STAT) signal transduction pathways. After pAg stimulation, purified Vγ9Vδ2 T cells from peripheral blood (PB) CTRL, PB MM and BM MM has been tested by western blot analysis for the expression of several intracellular proteins: Ras, phospho-ERK1/2, ERK1/2, phospho-Akt, Akt, phospho- JAK1, JAK1, phospho-STAT1, STAT1, phospho-STAT3, STAT3. Vγ9Vδ2 T cells isolated from BM MM and PB MM showed a remarkable down-modulation of pAKT, a key player of PD-1-mediated signal transduction, and pJAK-1 and pSTAT1, both involved in TIM-3-mediated signaling pathway. Morever, we observed a significantly reduced expression of the transcription factor T-bet, the downstream target gene of pSTAT1, selectively in Vγ9Vδ2 T cells isolated from the tumor site, suggesting that low T-bet expression is a further hallmark of BM Vγ9Vδ2 T cells exhaustion.Altogether, our findings allow to identify potential molecular mechanisms responsible for the poor efficacy of single immune checkpoint blockade in the tumor microenvironment and to design rational combination therapeutic strategy to be applied to the different clinical settings. DisclosuresBoccadoro:Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Massaia:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Novartis: Research Funding.

Combined OX40 Agonist and PD-1 Inhibitor Immunotherapy Improves the Efficacy of Vascular Targeted Photodynamic Therapy in a Urothelial Tumor Model.

Purpose: Vascular targeted photodynamic therapy (VTP) is a nonsurgical tumor ablation approach used to treat early-stage prostate cancer and may also be effective for upper tract urothelial cancer (UTUC) based on preclinical data. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. Experimental design: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. Results: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and prolonged survival to a greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. Conclusions: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.

Safety and Efficacy of PD-1/PD-L1 inhibitors combined with radiotherapy in patients with non-small-cell lung cancer: a systematic review and meta-analysis.

BackgroundA combination of programmed cell death protein‐1 (PD‐1)/programmed cell death ligand‐1 (PD‐L1) inhibitors and radiotherapy (RT) is increasingly being used to treat non‐small‐cell lung cancer (NSCLC). However, the safety and efficacy of this approach remains controversial. We performed a systematic review and meta‐analysis to summarize the related research.MethodsWe searched the China Biology Medicine, EMBASE, Cochrane Library, and PubMed databases for all the relevant studies. The Stata software, version 12.0 was used for the meta‐analysis.ResultsThe study included 20 clinical trials that enrolled 2027 patients with NSCLC. Compared with non‐combination therapy, combination therapy using PD‐1/PD‐L1 inhibitors and RT was associated with prolonged overall survival (OS) (1‐year OS: odds ratio [OR] 1.77, 95% confidence interval [CI] 1.35–2.33, p = 0.000; 2‐year OS: OR 1.77, 95% CI 1.35–2.33, p = 0.000) and progression‐free survival (PFS) (0.5‐year PFS: OR 1.83, 95% CI 1.13–2.98, p = 0.014; 1‐year PFS: OR 2.09, 95% CI 1.29–3.38, p = 0.003; 2‐year PFS: OR 2.47, 95% CI 1.13–5.37, p = 0.023). Combination therapy also improved the objective response rate (OR 2.76, 95% CI 1.06–7.19, p = 0.038) and disease control rate (OR 1.80, 95% CI 1.21–2.68, p = 0.004). This meta‐analysis showed that compared with non‐combination therapy, combination therapy using PD‐1/PD‐L1 inhibitors and RT did not increase the serious adverse event rates (≥grade 3); however, this approach increased the rate of grade 1–2 immune‐related or radiation pneumonitis. Subgroup analyses revealed that the sequence of PD‐1/PD‐L1 inhibitors followed RT outperformed in which concurrent PD‐1/PD‐L1 inhibitor and RT followed PD‐1/PD‐L1 inhibitor. Combination of stereotactic body RT or stereotactic radiosurgery with PD‐1/PD‐L1 inhibitors may be more effective than a combination of conventional RT with PD‐1/PD‐L1 inhibitors in patients with advanced NSCLC.ConclusionCombination therapy using PD‐1/PD‐L1 inhibitors and RT may improve OS, PFS, and tumor response rates without an increase in serious adverse events in patients with advanced NSCLC. However, combination therapy was shown to increase the incidence of mild pneumonitis.

Initial Experience With Palliative “QUAD-SHOT” Radiotherapy With Concurrent And Adjuvant PD-1 Inhibitor For Recurrent And/Or Metastatic Head And Neck Cancer

To analyze our initial institutional experience of palliative “QUAD-SHOT” radiotherapy with concurrent and adjuvant PD-1 inhibitor for recurrent and/or metastatic head and neck cancers. Our hypothesis is that the addition of immunotherapy to palliative radiation is safe and will result in effective disease control. IRB approved retrospective analysis of fifteen patients (pts) with incurable loco-regionally recurrent and/or metastatic head and neck cancer. All pts received palliative radiation therapy (RT) with the “QUAD-SHOT” regimen (3.7 Gy twice daily over 2 consecutive days at 3-week intervals per cycle, total of 3 cycles) with concurrent and adjuvant PD-1 inhibitor (pembrolizumab q3w or nivolumab q2w) between 10/2016 – 10/2019. Pts continued on adjuvant immunotherapy until disease progression was documented. Tumor response was documented by radiologic imaging and physical examination. Toxicity was graded utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Data analysis was performed using SPSS statistical software version 25.0. Survival analysis for loco-regional control (LRC), Overall Survival (OS), Progression Free Survival (PFS), and Distant Metastasis Free Survival (DMFS) was performed using the Kaplan-Meier method. Median age was 64 years (range, 52 – 97 years). All pts had an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2. The most common histology was squamous cell carcinoma (93%). None of the pts had HPV-related disease. Six pts (40%) received prior RT (≥ 60 Gy) at the palliative site. All pts completed at least three “QUAD-SHOT” cycles and all received at least three infusions of concurrent and adjuvant PD-1 inhibitor, pembrolizumab (60%) or nivolumab (40%). The most common presenting symptom was pain (73%). Thirteen (87%) pts had palliation of their presenting symptom. Objective (complete or partial) response to therapy was 60%. Median OS was 7.1 months (range, 1.9 – 24.3 months), and median PFS was 6.5 months (range, 1.9 – 24.3 months). The 6-month LRC, OS, PFS, and DMFS were 100%, 86%, 80%, and 80%, respectively. The 12-month LRC, OS, PFS, and DMFS were 50%, 60%, 30%, and 46% respectively. Radiation Grade 3 toxicity in 3 pts (20%) consisted of mucositis (13%) and dermatitis (7%). The most common toxicity associated with PD-1 inhibitors was Grade ≥ 2 fatigue (53%). Abscopal effect was documented in 2 (13%) pts. Our analysis suggests that QUAD-SHOT palliative radiation with concurrent PD-1 inhibitor for incurable loco-regionally recurrent and/or metastatic squamous cell carcinoma of the head and neck is efficacious and well-tolerated in this group of pts with limited life expectancy. Further studies with larger number of pts are required to better define the optimal sequencing, number of cycles, and type of PD-1 inhibitor in this population.

Growth differentiation factor-15 slows the growth of murine prostate cancer by stimulating tumor immunity.

Growth Differentiation Factor-15 (GDF15) is a divergent TGF-beta superfamily cytokine that is overexpressed by most cancers and is induced by anticancer therapy. Transgenic and induced animal models suggest that it protects from cancer development but the mechanisms are uncertain. We investigated the role of immunity in GDF15 induced reduction in prostate cancer (PCa) growth. The C57BL/6 transgenic TRAMP prostate cancer prone mice were bred with mice that were immunodeficient and/or systemically overexpressed GDF15. We developed a novel orthotopic TRAMP PCa model in which primary TRAMP tumor cells were implanted into prostates of mice to reduce the study time. These mice were administered recombinant mouse GDF15, antibody to CD8, PD1 or their respective controls. We found that GDF15 induced protection from tumor growth was reversed by lack of adaptive immunity. Flow cytometric evaluation of lymphocytes within these orthotopic tumors showed that GDF15 overexpression was associated with increased CD8 T cell numbers and an increased number and proportion of recently activated CD8+CD11c+ T cells and a reduced proportion of "exhausted" CD8+PD1+ T cells. Further, depletion of CD8 T cells in tumor bearing mice abolished the GDF15 induced protection from tumor growth. Infusion of GDF15 into mice bearing orthotopic TRAMP tumor, substantially reduced tumor growth that was further reduced by concurrent PD1 antibody administration. GDF15 overexpression or recombinant protein protects from TRAMP tumor growth by modulating CD8 T cell mediated antitumor immunity and augments the positive effects of anti-PD1 blockers.

The Effect of Concurrent Stereotactic Body Radiation and Anti-PD-1 Therapy for Recurrent Metastatic Sarcoma.

Patients diagnosed with metastatic sarcoma have limited options for achieving both local and distant tumor control. While SBRT can achieve local control, distant response rates remain low. There is limited evidence demonstrating the safety and efficacy for combining SBRT with concurrent PD-1 checkpoint blockade in metastatic sarcoma. In this prospective case-series, we examined five patients with metastatic sarcoma on pembrolizumab treated concurrently with SBRT from July 1, 2016-October 30, 2018. Acute and chronic toxicity were recorded using Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). SBRT-treated tumor control was assessed using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). With median follow-up of 14.9 months, three patients with undifferentiated pleomorphic sarcoma, one with intimal, and one with chondroblastic osteosarcoma received SBRT with concurrent pembrolizumab to 10 sites of metastatic disease. No grade 5 toxicities were observed. There was a single incidence of transient grade 4 lymphopenia which resolved without intervention. Grade 3 toxicities included anemia, thrombocytopenia, lymphopenia and colitis. One tumor demonstrated local progression after SBRT, and all others remained stable or with response. In conclusion, combining SBRT with PD-1 inhibition appeared to be safe in this patient population. Expected high rates of treated-tumor local control after SBRT were observed. Two of five patients demonstrated either enhanced local tumor regression, or possible abscopal effect.

Combined OX40 agonist and PD-1 inhibitor immunotherapy improves the efficacy of vascular targeted photodynamic therapy in a urothelial tumor model.

e17004 Background: In patients with low-grade, small upper tract urothelial carcinomas (UTUC), as well as those in whom preservation of kidney function is critical, local ablative therapies such as vascular targeted photodynamic (VTP) therapy have emerged as a means of reducing treatment-related morbidity. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. Methods: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. Results: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and metastasis and prolonged survival to a much greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. Conclusions: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.

A Retrospective Review of Unresectable Stage III and Stage IV Oligometastatic Cancers Treated with Concurrent PD-1 Inhibition and Ablative Radiotherapy

A Retrospective Review of Unresectable Stage III and Stage IV Oligometastatic Cancers Treated with Concurrent PD-1 Inhibition and Ablative Radiotherapy

Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer—The ETOP NICOLAS trial

ObjectivesChemo-radiotherapy (CRT) and concurrent PD-1 inhibition has shown promising results in pre-clinical models. So far, the feasibility of delivering concurrent CRT and PD-1/PD-L1 inhibition has never been assessed in a clinical trial. Material and methodsNICOLAS is a phase-II trial evaluating the safety and efficacy of nivolumab combined with CRT in stage III NSCLC. Patients received 3 cycles of platinum-based chemotherapy and concurrent RT (66 Gy/33fractions). Nivolumab started concurrently with RT. The primary endpoint was 6-month post-RT rate of grade-≥3-pneumonitis. A formal interim safety analysis (IA) was scheduled when the first 21 patients reached 3 months follow-up post-RT. An early positive safety conclusion would be reached at IA if there were no grade ≥3-pneumonitis in those patients. Efficacy evaluation was planned provided the safety conclusion was reached. Results and conclusionAs of 13 December 2018, 82 patients were recruited with median follow-up of 13.4 months. The most frequent adverse events (AEs) were anaemia, fatigue and pneumonitis. No unexpected AEs or increased toxicities were observed. For the first 21 patients, no grade-≥3-pneumonitis was observed by the end of the 3-month post-RT follow-up period.The early safety IA provides evidence that the addition of nivolumab to concurrent CRT is safe and tolerable regarding the 6-month rate of pneumonitis grade ≥3 at the one-sided significance level of 5%. Following that, the 1-year progression-free survival will be evaluated in an expanded patient cohort. NICOLAS trial creates the opportunity for assessing the activity of the combination of checkpoint with concurrent CRT in larger prospective trials for locally advanced NSCLC.

Reirradiation and PD-1 inhibition with nivolumab for the treatment of recurrent diffuse intrinsic pontine glioma: a single-institution experience

Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive brain tumor with no known cure. Reirradiation (reRT) at recurrence can prolong survival. The impact of irradiation may be heightened when combined with PD-1 inhibition. We describe our experience using reRT, with or without PD-1 inhibition, in a cohort of patients with recurrent DIPG. We performed a retrospective cohort analysis of children who received reRT with or without concomitant PD-1 inhibition for recurrent DIPG at a single institution between 2005 and 2016. We compared progression-free (PFS) and overall survival (OS) between those who received reRT alone or in combination with PD-1 inhibition. We then compared reRT to a cohort of patients who did not receive reRT. Thirty-one patients were included (8-reRT with nivolumab; 4-reRT alone; 19-no reRT). Patients who received reRT had prolonged OS compared to no reRT (22.9 months-reRT with nivolumab; 20.4months-reRT alone; 8.3months-no reRT; p < 0.0001). Patients who received reRT with nivolumab vs. reRT only had slightly prolonged OS from diagnosis and from reRT (22.9 vs. 20.4months for time from diagnosis; 6.8 vs. 6.0months for time from reRT). All patients receiving reRT with or without nivolumab tolerated the therapy without acute or late toxicity. Our experience demonstrates the tolerability of reRT with concurrent PD-1 inhibition for recurrent DIPG and suggests that combination therapy may offer survival benefit. Future prospective studies are needed to confirm the benefits of this combination therapy.

A Sampling of Highlights from the Literature

NKs calling in the DCs (by Penn1234567, based on L. Kohidai image, via Wikimedia Commons)Stimulatory DCs are pivotal in shaping immune responses to tumors. These cells are recruited to the melanoma tumor microenvironment by NK cell–secreted Flt3L, which promotes production of stimulatory DCs. NK cells form synapse-like engagements with DCs that, in turn, increase DC survival. The frequency of these cell types correlates with anti–PD-1 responsiveness.Barry KC, …, Krummel MF. Nat Med 2018 Jun 25. DOI: 10.1038/s41591-018-0085-8.Controlling the tumor microenvironment (by skeeze via Pixabay)By comparing tumor cell clones derived from different cells of a pancreatic ductal adenocarcinoma, Li and colleagues find that only some tumors formed from such clones acquire infiltrating T cells, whereas others that produce CXCL1 suppress infiltration. Mixing tumor cell clones that support infiltration with those that do not showed the dominance of suppressive clones. Alonso and colleagues examine recognition of tumor neoantigens in a genetically driven mouse tumor model of lung adenocarcinoma and find that naïve CD4+ T cells are primed in the draining lymph nodes but, rather than become effector cells, either become anergic or are induced to become peripheral Tregs. Thus, tumors appear to promote conditions that recapitulate the mechanisms responsible for peripheral self-tolerance.Li J, …, Stanger BZ. Immunity 2018 Jun 26. DOI: 10.1016/j.immuni.2018.06.006.Alonso R, …, Lantz O. Nat Commun 2018 May 29. DOI: 10.1038/s41467-018-04524-x.Selection and survival (by Elembis via Wikimedia Commons)Tumor cell diversity can result from cancer immunoediting. Multiple peritoneal sites from 38 patients with high-grade serous ovarian cancer were assessed for immunologic features that affect tumor cell diversity. Tumor-infiltrating immune cells select for tumor cell clones that then escape immune detection, which can result in spread of tumors lacking infiltrates and resistant to immunotherapy.Zhang AW, …, Shah SP. Cell 2018 Jun 14;173:1755–1769.e22.PD-1 blockade could help drain inhibitory subset accumulation (by Semevent via Pixabay)CD4+Foxp3− cells with high expression of PD-1 accumulate in the tumors of patients with melanoma and non–small cell lung cancer, where they inhibit antitumor responses in a PD-1/PD-L1–dependent manner. This inhibitory CD4+ population has follicular helper T cell–like characteristics. CTLA-4 blockade enhances accumulation of these cells, which interferes with antitumor responses, and the accumulation can potentially be abrogated by concurrent PD-1 blockade.Zappasodi R, …, Wolchok JD. Cancer Cell 2018 Jun 11;33:1017–1032.e7.Surgery-induced tumor outgrowth linked to wound-healing response (by L. Moreno, David Grant USAF Medical Center)Early recurrence of breast cancer after surgical resection is not uncommon, raising questions if surgical tumor disruption induces spread or promotes outgrowth of dormant tumors. Using a novel orthotopic mouse model, outgrowth is now linked directly to the surgery-induced, wound-healing inflammatory response. Dormancy is maintained by T cells, and the increase in tumor outgrowth accompanying surgery could be combated with anti-inflammatories. Thus, surgery has systemic effects that can interfere with antitumor responses and promote tumor outgrowth.Krall JA, …, Weinberg RA. Sci Transl Med 2018 Apr 11;10: eaan3464.Identifying new antitumor cells (by ho7dog via Pixnio)CD8+ T cells are crucial for antitumor activity. Thommen and colleagues found that a subset of CD8+ T cells expressing high amounts of PD-1 are functionally and transcriptionally distinctive. These cells, which accumulate in non–small cell lung cancer, predict survival and strong antitumor responses in patients treated with anti–PD-1. Using single-cell RNAseq, Savas and colleagues identified a population of tissue-resident memory-like CD103+CD8+ T cells that highly express checkpoint proteins amidst breast cancer–infiltrating T cells. These cells correlated significantly with a better prognosis for patients with triple-negative breast cancer, making the cells targets for modulation.Thommen DS, …, Zippelius A. Nat Med 2018 Jun 11. DOI: 10.1038/s41591-018-0057-z.Savas P, …, Loi S. Nat Med 2018 Jun 25. DOI: 10.1038/s41591-018-0078-7.

Concurrent, but not sequential, PD-1 blockade with a DNA vaccine elicits anti-tumor responses in patients with metastatic, castration-resistant prostate cancer.

T-cell checkpoint inhibitors have demonstrated dramatic clinical activity against multiple cancer types, however little activity in patients with prostate cancer. Conversely, an anti-tumor vaccine was approved for the treatment of prostate cancer, having demonstrated an improvement in overall survival, despite few objective disease responses. In murine studies, we found that PD-1 expression on CD8+ T cells increased following anti-tumor vaccination, and that PD-1/PD-L1 blockade at the time of immunization elicited greater anti-tumor responses. Based on these data we initiated a pilot trial evaluating the immunological and clinical efficacy of a DNA encoding prostatic acid phosphatase (PAP) when delivered in combination with pembrolizumab. 26 patients were treated for 12 weeks with vaccine and received pembrolizumab either during this time or during the subsequent 12 weeks. Adverse events included grade 2 and 3 fatigue, diarrhea, thyroid dysfunction, and hepatitis. Median time to radiographic progression was not different between study arms. 8/13 (62%) of patients treated concurrently, and 1/12 (8%, p=0.01) of patients treated sequentially, experienced PSA declines from baseline. Of these, two were over 50% and one was a complete PSA response. No confirmed CR or PR were observed, however 4/5 patients treated concurrently had measurable decreases in tumor volume at 12 weeks. PSA declines were associated with the development of PAP-specific Th1-biased T cell immunity and CD8+ T cell infiltration in metastatic tumor biopsy specimens. These data are the first report of a clinical trial demonstrating that the efficacy of an anti-tumor vaccine can be augmented by concurrent PD-1 blockade.

Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-RT regimen in unresectable locally advanced NSCLC: The ETOP NICOLAS phase II trial.

8510Background: The feasibility of combined chemo-radiotherapy (chemo-RT) and concurrent PD-1 inhibition is of high scientific interest and has shown promising results in pre-clinical models. So fa...

(P09) Combined Use of Radiosurgery With Concurrent PD-1/PD-L1 Inhibition For Metastatic Brain Lesions of NSCLC

Lung cancer is the leading cause of cancer death worldwide. The FDA first approved targeted PD-1/PD-L1 therapy for the treatment of advanced NSCLC in early 2015, and immunotherapies (IT) are becoming common in the setting of metastatic NSCLC. Some have hypothesized synergistic local and distant effects between stereotactic radiotherapy and IT, however data supporting safety and efficacy of their concurrent use has yet to be reported in the setting of SRS for brain metastasis from NSCLC. We evaluated overall survival (OS), time to intracranial progression (ICP), and acute adverse events (AEs) within our institution retrospective experience of PD-1/PD-L1 inhibitors and stereotactic radio surgery (SRS) for metastatic brain lesions of NSCLC. This study included all patients with brain metastases from NSCLC treated concurrently or sequentially with SRS and either PD-1 or PD-L1 inhibitors at our institution from October 2014 - June 2016. SRS was delivered using the Pefexion - GammaKnife. The time to ICP was measured from the time of SRS until radiological evidence of ICP by MRI. OS was calculated from the time of the first SRS treatment until death. Concurrent treatment was defined as receiving SRS within 30 days before or after immunotherapy. Comparison of these endpoints was made against patients who received radiation greater than 90 days prior to PD-1/PD-L1 inhibitors defined as non-concurrent or sequential therapy. Comparisons of time to ICP and OS were performed using the log-rank test and Kaplan-Meier estimated survival estimates. We identified twelve patients, who were treated with concurrent PD-1/PD-L1 inhibitors and SRS. Of these 12 patients, 2 received an additional SRS treatment for brain metastases while still receiving IT. Six of the 12 patients received SRS for 1 brain lesion while on IT; the other six patients had a range of 2-6 lesions treated in one session. Sixteen patients were identified that had received IT greater than 90 days after SRS intervention. Both time to ICP and OS were performed on a patient only basis calculating time from first SRS intervention. The median follow up was 10 months. OS was not statistically different between concurrent vs. non-concurrent groups with a median OS of 15 (1-20) months vs. 23.5 (7-54) months respectively (p=0.43). Time to ICP did not differ between our groups with time to ICP of 5.8 (1.1 - 20.5) months with concurrent therapy vs. 19.4 (1.4 - 54) months with non-concurrent therapy (p=0.70). Eight of 12 patients in the concurrent therapy group denied any acute AES, two patients reported a headache, one reported dizziness and another patient reported numbness. Our data suggest that concurrent use of SRS for brain metastases of NSCLC with PD-1/PD-L1 inhibitors may not be associated with an increase in acute AEs nor does it affect the time to ICP or OS. Time to ICP or OS after SRS were similar between patients who received concurrent vs. non-concurrent IT in our analysis and our reported median survival times and time to ICP is consistent with historically reported outcomes for patients treated with SRS alone.

The Impact of the Timing of PD-1 Inhibition on Disease Control for Brain Metastases Treated with Stereotactic Radiosurgery

PD-1 inhibitors have shown single-agent activity against brain metastases, but their synergy with radiosurgery is unknown. The purpose of this study was to evaluate whether the timing of anti-PD-1 therapy when combined with stereotactic radiosurgery (SRS) for brain metastases may affect treatment outcomes. For this retrospective study, an institutional database of patients with intracranial metastases treated with SRS between 2014 and 2016 was reviewed for individuals who had received immunotherapy (IT) with the PD-1 inhibitors Nivolumab and Pembrolizumab. Patients were divided into two cohorts based on the timing of IT. Individuals were classified as having received concurrent IT if they received anti-PD-1 agents prior to or within within three weeks of SRS. Adjuvant IT was defined as administration of PD-1 inhibitors more than three weeks after SRS. The student's t-test aFisher’s exact test were utilized to compare baseline clinical and demographic covariates. The Kaplan-Meier method and log-rank test were then used to estimate and compare local control (LC), distant brain control (DBC), and overall survival (OS) between these two cohorts. Cox proportional hazards models were used to identify predictors of these outcome metrics. Fifty patients were eligible for this analysis, and the majority had been diagnosed with either metastatic non-small cell lung cancer (NSCLC, n=24) or melanoma (n=22). Twenty-seven (54%) received concurrent IT, and 23 (46%) received adjuvant IT (median time between SRS and adjuvant IT: 3.1 months, range 0.9 months – 11.9 months). Concurrent CTLA-4 was administered along with PD-1 blockade in only 2 patients (4%). Twelve patients (24%) had previously undergone whole brain radiation therapy (WBRT), and 37 patients (74%) had received prior chemotherapy. Mean follow-up time was 7.1 months. Baseline clinical and demographic characteristics were comparable between the two groups. At six months, LC was 100% for patients receiving concurrent IT and 76% in the adjuvant IT group (p=0.04). Similarly, DBC was 71% and 41%, respectively ( p=0.02). OS was not significantly different between the two groups (p = 0.36). On multivariate analysis, controlling for age, performance status, and prior WBRT, concurrent IT was predictive of both improved LC (HR = 0.07, p = 0.049) and improved DBC (HR = 0.30, p = 0.02). Subset analysis demonstrates that improved DBC with the administration of concurrent IT was seen in patients with both melanoma (p=0.02) and NSCLC (p=0.04). In this heavily pre-treated cohort undergoing radiosurgery for brain metastases, concurrent PD-1 IT administered within three weeks of SRS appears to improve LC and DBC when compared to adjuvant PD-1 blockade.