Antibody Monotherapy Research Articles

Combination therapy with anti-PD-1 or PD-1 antibody alone in pediatric patients with relapsed or refractory cancer.

e22004 Background: There is limited experience of PD-1 combined with other therapies in children. We aimed to explore the antitumor activity and safety of PD-1 antibody monotherapy or combination with other regimens in relapsed or refractory pediatric cancer. Methods: This was an observational retrospective study performed at two academic medical centers (Sun Yat-sen University Cancer Center and Nanfang Hospital, Southern Medical University) The primary objective of this study was to describe the overall response rate (ORR) and disease control rate (DCR). Secondary objectives included characterizing toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 as well as describing progression free survival (PFS) and overall survival (OS). Results: Of the 22 pediatric cancer patients who received PD-1 inhibitors, the median follow-up for all patients after the commencement of PD-1 therapy with or without other regimens was 12.3 months (0-43 months). The objective response rate (ORR) and disease control rate (DCR) of the 6 patients with HL were 83.3% (3CR and 2PR) and 100%, respectively. No objective response was observed in patients with melanoma or Burkitt lymphoma evaluated in this study. For patients treated with PD-1 inhibitor combination therapy, PD-1 antibody combined with decitabine showed potential efficacy in advanced pediatric cancer patients. One of the Three of patients who received PD-1 combined with decitabine achieved CR and another two other patients achieved PR. At the data cutoff, 10 of the 13 (76.9%) patients achieved disease control as the best objective response. The median PFS and OS were 90 days (95%CI: 10.733-169.267) and 158 days (95%CI: 131.514-184.486) respectively. There were no severe treatment-related adverse events (TRAEs) directly attributed to PD-1 monotherapy. The severe TRAEs are due to chemotherapy in the combination regimen. Conclusions: PD-1 monotherapy demonstrated antitumor activity in a population of pediatric patients with HL. The regimen of PD-1 inhibitor combined with decitabine showed potential in treating with pediatric cancer patients.

A phase I study of SHR7390 plus camrelizumab in advanced/metastatic colorectal cancer.

e15553 Background: PD-1 antibody monotherapy has shown durable response in colorectal cancer (CRC) patients (pts) with microsatellite instability (MSI) high status, who account for only 10–15% of all CRC pts. Preclinical studies revealed that inhibition of MAPK pathway with MEK inhibitors can increase T-cell infiltration into tumors and therefore might enhance the antitumor activity of immune checkpoint inhibitor. Thus, this study was conducted to evaluate the safety and antitumor activity of SHR7390, a MEK1/2 inhibitor, plus camrelizumab (anti-PD-1) in pts with CRC. Methods: In this single-arm, open-label, phase I study, pts with treatment-refractory advanced or metastatic CRC were enrolled to receive SHR7390 in an accelerated titration scheme at doses of 0.125, 0.25, and 0.5 mg orally qd, plus camrelizumab at a fixed dose of 200 mg IV q2w. Eligible pts were given a single dose of SHR7390, observed for 7–10 days, and then treated continuously with SHR7390 and camrelizumab in 28-day treatment cycles until disease progression, intolerable toxicities, or withdrawal of consent. A recommended dose for expansion was determined based on the safety and tolerability of the dose escalation stage. The primary endpoints were dose limiting toxicity (DLT) and maximum tolerated dose (MTD). This study is registered with ClinicalTrials.gov, number NCT03182673. Results: At data cutoff on May 30, 2020, 22 pts were enrolled. The median follow-up duration was 6 months. Seven pts had received ≥3 lines of prior treatment. MSI status were available in 21 pts (MSS/MSI-L, n = 18; MSI-H, n = 3). There were two pts each in the SHR7390 0.125 and 0.25 mg cohorts, and 0.5 mg cohort was expanded to 18 pts. One DLT (grade 3 rash) was reported in a pt in the 0.5 mg cohort and the MTD was not reached. Grade 3–4 treatment-related adverse events (TRAEs) were rash (n = 4), increased lipase, oedema peripheral, face oedema, and anemia (n = 1 each). One pt reported a grade 5 TRAE (increased intracranial pressure). Five pts (23%) achieved partial response (0.125 and 0.25 mg cohorts, n = 1 each; 0.5 mg cohort, n =3), including one out of three pts with MSS/MSI-L & BRAF mutant tumors (response lasting 13 months), one out of 15 pts with MSS/MSI-L & BRAF wild type tumors (response lasting 8 months), and all three pts with MSI-H tumors (responses lasting 31, 11, and 10 months, respectively). Three pts with MSS/MSI-L achieved stable disease, and the overall disease control rate reached 36%. Conclusions: SHR7390 plus camrelizumab showed a tolerable safety profile. Preliminary clinical activity was reported regardless of BRAF and MSI status, and future studies are warranted to further evaluate these results. Clinical trial information: NCT03182673.

Impact of Bamlanivimab Monoclonal Antibody Treatment on Hospitalization and Mortality Among Nonhospitalized Adults With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BackgroundMonoclonal antibody treatment may prevent complications of coronavirus disease 2019 (COVID-19). We sought to quantify the impact of bamlanivimab monoclonal antibody monotherapy on hospitalization and mortality among outpatients at high risk of COVID-19 complications.MethodsIn this observational study we compared outpatients who received bamlanivimab monoclonal antibody from December 9, 2020 to March 3, 2021 to nontreated patients with a positive polymerase chain reaction or antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the same period who were eligible for monoclonal antibody treatment. The primary outcome was 28-day hospitalization or all-cause mortality, and the secondary outcome was hospitalization or emergency department visit without hospitalization. The risk-adjusted odds of study outcomes comparing bamlanivimab treated and untreated patients was determined using 1:5 propensity matching and multivariable logistic regression.ResultsAmong 232 patients receiving bamlanivimab matched with 1160 comparator patients, the mean age was 67 years, 56% were female, and 196 (14%) of patients experienced hospitalization or mortality. After adjustment for propensity to receive treatment, bamlanivimab treatment was associated with a significantly reduced risk-adjusted odds of hospitalization or mortality within 28 days (odds ratio [OR], 0.40; 95% confidence interval [95% CI], 0.24–0.69; P < .001). Bamlanivimab treatment was also associated with a significantly lower risk adjusted odds of hospitalization or emergency department visit without hospitalization (OR, 0.54; 95% CI, 0.35–0.82; P = .004). The results were most strongly associated with patients age 65 years and older.ConclusionsBamlanivimab monoclonal antibody monotherapy was associated with reduced hospitalizations and mortality within 28 days among outpatients with mild to moderate COVID-19.Use of bamlanivimab monotherapy for outpatients with mild to moderate COVID-19 infection was associated with reductions in hospitalizations and mortality within 28 days. Benefit was strongest in those age 65 years or older

Multifunctionality of CD8+ T cells and PD‐L1 expression as a biomarker of anti‐PD‐1 antibody efficacy in advanced melanoma

Anti-programmed cell death protein-1 (PD-1) antibodies have become a standard treatment for advanced melanoma. However, a predictive biomarker for assessing the efficacy of anti-PD-1 antibodies has not been identified. In cancer, CD8+ T cells specific for tumor antigens undergo repeated T-cell receptor stimulation due to the persistence of cancer cells and gradually lose their ability to secrete interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). We aimed to evaluate multi-cytokine production and immune exhaustion of peripheral CD8+ T cells in melanoma patients treated with anti-PD-1 antibodies. Twenty-four melanoma patients treated with nivolumab were included. Effector cytokine production (IL-2, TNF-α, and IFN-γ) and expression of an exhaustion marker (PD-1) in patients' CD8+ cells were analyzed with flow cytometry. The relationships between parameters such as the neutrophil-to-lymphocyte ratio (NLR) and clinical response to nivolumab were examined. Immunohistochemistry for programmed death-ligand 1 (PD-L1) expression in tumor cells and tumor-infiltrating lymphocytes (TILs) and analysis of their association with clinical response were performed. The clinical response rate to nivolumab was 29%. Regarding TILs, NLR, and several other parameters, no significant difference was found between responders and non-responders. The responder group showed an increase in the percentage of PD-1+ CD8+ /TNF-α+ IFN-γ+ or PD-1+ CD8+ /IFN-γ+ IL-2+ TNF-α+ T cells compared to non-responders. Positivity for PD-L1 expression was significantly higher in the responder group than the non-responder group. In advanced melanoma, the percentage of multifunctional CD8+ PD-1+ T cells and PD-L1 expression in the tumors may be a biomarker for a good response to anti-PD-1 antibody monotherapy.

Preclinical Evaluation of Recombinant Human IL15 Protein Fused with Albumin Binding Domain on Anti-PD-L1 Immunotherapy Efficiency and Anti-Tumor Immunity in Colon Cancer and Melanoma.

Simple SummaryIn this manuscript, we reported that a newly developed recombinant human IL15 fused with albumin binding domain (hIL15-ABD) showed superior biological half-life, pharmacokinetic and anti-tumor immunity than wild-type (WT) hIL15. Our hIL-15-ABD can effectively enhance anti-tumor efficacy of anti-PD-L1 on colon cancer and melanoma animal models. The anti-tumor potential of hIL-15-ABD was associated with tumor microenvironment (TME) regulation, including the activation of NK cells and CD8+ T cells, the reduction of immunosuppressive cells (MDSCs and Tregs) and the suppression of immunosuppressive factors (IDO, FOXP3 and VEGF). In conclusion, our new hIL15-ABD combined with anti-PD-L1 antibody increased the activity of anti-tumor effector cells involved in both innate and adaptive immunities, decreased the TME’s immunosuppressive cells, and showed greater anti-tumor effect than that of either monotherapy. We suggested hIL15-ABD as the potential complementary agent may effectively augment the therapeutic efficacy of anti-PD-L1 antibody in colon cancer and melanoma model.Anti-PD-L1 antibody monotherapy shows limited efficacy in a significant proportion of the patients. A common explanation for the inefficacy is a lack of anti-tumor effector cells in the tumor microenvironment (TME). Recombinant human interleukin-15 (hIL15), a potent immune stimulant, has been investigated in clinical trial with encouraging results. However, hIL15 is constrained by the short half-life of hIL15 and a relatively unfavorable pharmacokinetics profile. We developed a recombinant fusion IL15 protein composed of human IL15 (hIL15) and albumin binding domain (hIL15-ABD) and explored the therapeutic efficacy and immune regulation of hIL-15, hIL15-ABD and/or combination with anti-PD-L1 on CT26 murine colon cancer (CC) and B16-F10 murine melanoma models. We demonstrated that hIL15-ABD has significant inhibitory effect on the CT26 and B16-F10 tumor growths as compared to hIL-15. hIL-15-ABD not only showed superior half-life and pharmacokinetics data than hIL-15, but also enhance anti-tumor efficacy of antibody against PD-L1 via suppressive effect on accumulation of Tregs and MDSCs and activation of NK and CD8+T cells. Immune suppressive factors including VEGF and IDO were also decreased by combination treatment. hIL15-ABD combined with anti-PD-L1 antibody increased the activity of anti-tumor effector cells involved in both innate and adaptive immunities, decreased the TME’s immunosuppressive cells, and showed greater anti-tumor effect than that of either monotherapy.

The Optimal Dose of Tacrolimus in Combination Therapy with an Anti-TNFα Antibody in a Mouse Colitis Model.

An attempt to use combination therapy with anti-tumor necrosis factor α (TNFα) antibodies and tacrolimus (TAC) has been tried to induce remission in ulcerative colitis (UC). However, the optimal dose of TAC in combination therapy with anti-TNFα antibodies (TAC + anti-TNFα therapy) remains unclear. We examined the efficacy of various doses of TAC + anti-TNFα therapy in a mouse colitis model. Dextran sulfate sodium induced colitis model mice were divided into an anti-TNFα antibody monotherapy group and the groups that received various doses of TAC + anti-TNFα therapy. The nuclear factor expression of activated T-cells, cytoplasmic 1 (NFATc1) in the nuclei and the mRNA expression of inflammatory cytokines were assessed by immunohistochemistry and RT-PCR, respectively. The serum anti-TNFα antibody concentration was measured with an enzyme-linked immunosorbent assay. The colon length and histological severity were significantly improved in the groups that received any dose of TAC + anti-TNFα therapy. The nuclear expression of NFATc1 was inversely proportional to the administered doses of TAC. The expression levels of inflammatory cytokines tended to decrease in proportion to the dose of TAC. The serum concentration of anti-TNFα antibodies in the high-dose TAC + anti-TNFα therapy was significantly higher than those in the other groups. Low-dose TAC exerted its immunosuppressive effect on T-cells, and additionally, high-dose TAC maintained the serum anti-TNFα antibody concentration. When administered in combination with anti-TNFα antibodies, the dose of TAC should be adjusted according to the disease severity.

Human Monoclonal Antibody Cocktail for the Treatment or Prophylaxis of Middle East Respiratory Syndrome Coronavirus.

BackgroundREGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells.MethodsPreclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation.ResultsPreclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic.ConclusionsREGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.

Zika virus oncolytic activity requires CD8+ T cells and is boosted by immune checkpoint blockade.

Glioblastoma multiforme (GBM) is a fatal human cancer in part because GBM stem cells are resistant to therapy and recurrence is inevitable. Previously, we demonstrated Zika virus (ZIKV) targets GBM stem cells and prevents death of mice with gliomas. Here, we evaluated the immunological basis of ZIKV-mediated protection against GBM. Introduction of ZIKV into the brain tumor increased recruitment of CD8+ T and myeloid cells to the tumor microenvironment. CD8+ T cells were required for ZIKV-dependent tumor clearance because survival benefits were lost with CD8+ T cell depletion. Moreover, while anti–PD-1 antibody monotherapy moderately improved tumor survival, when coadministered with ZIKV, survival increased. ZIKV-mediated tumor clearance also resulted in durable protection against syngeneic tumor rechallenge, which also depended on CD8+ T cells. To address safety concerns, we generated an immune-sensitized ZIKV strain, which was effective alone or in combination with immunotherapy. Thus, oncolytic ZIKV treatment can be leveraged by immunotherapies, which may prompt combination treatment paradigms for adult patients with GBM.

The clinicopathological significance and predictive value for immunotherapy of programmed death ligand-1 expression in Epstein-Barr virus-associated gastric cancer

ABSTRACT The effect of anti-programmed cell death 1 (PD-1) antibody in Epstein-Barr virus-associated gastric cancer (EBVaGC) was debatable, and no predictive biomarkers for efficacy have been reported. Public reports on anti-PD-1 antibody monotherapy-treated EBVaGC with available programmed death ligand-1 (PD-L1) expression status were summarized and analyzed. Relevance with clinicopathologic characteristics of PD-L1 expression by immunohistochemistry was analyzed in 159 patients diagnosed with EBVaGC. Relevance with genomic transcriptome and mutation profile of PD-L1 status in EBVaGC was assessed with three datasets, the cancer genome atlas (TCGA), Gene Expression Omnibus (GEO) GSE51575, and GSE62254. Based on the data from 8 reports, patients with positive PD-L1 expression (n = 30) had significantly superior objective response rate (ORR) than patients with negative PD-L1 expression (n = 9) (63.3% vs. 0%, P = .001) in EBVaGC receiving anti-PD-1 antibody monotherapy. PD-L1 positivity was associated with less aggressive clinicopathological characteristics and was an independent predictor for a longer disease-free survival (hazard ratio [HR] and 95% CI: 0.45 [0.22–0.92], P = .03) and overall survival (HR and 95% CI: 0.17 [0.06–0.43], P < .001). Analysis of public EBVaGC transcriptome and mutation datasets revealed enhanced immune-related signal pathways in PD-L1high EBVaGC and distinct mutation patterns in PD-L1low EBVaGC. PD-L1 positivity indicates a subtype of EBVaGC with ‘hot’ immune microenvironment, lower aggressiveness, better prognosis, and higher sensitivity to anti-PD-1 immunotherapy.

Association of Preexisting Interstitial Lung Abnormalities With Immune Checkpoint Inhibitor–Induced Interstitial Lung Disease Among Patients With Nonlung Cancers

Immune checkpoint inhibitor-induced interstitial lung disease (ICI-ILD) is clinically serious and life-threatening. Preexisting interstitial lung abnormalities have been shown to be risk factors for ICI-ILD in patients with lung cancer. To evaluate whether interstitial lung abnormalities are associated with ICI-ILD in patients with nonlung cancers. This cohort study was conducted between December 2015 and May 2019 at Hiroshima University Hospital. A total of 199 consecutive patients with head and neck cancer, malignant melanoma, oral cavity cancer, urological cancer, and gastrointestinal cancer who received anti-programmed cell death 1 (PD-1) antibody monotherapy were included. Data analysis was conducted from December 2015 to May 2019. The associations between potential risk factors and the development of ICI-ILD were examined. Information on patient characteristics before antibody administration, including chest computed tomography findings, was obtained. The diagnosis of ICI-ILD was defined as abnormal computed tomography shadows occurring during treatment with anti-PD-1 antibodies. A total of 199 patients were enrolled in the study. The median (range) age was 66 (20-93) years, and most patients (133 [66.8%]) were men. Nineteen patients (9.5%) developed ICI-ILD. There was no significant difference in the baseline characteristics between patients with and without ICI-ILD. The logistic regression analyses revealed that interstitial lung abnormalities were associated with increased risk of ICI-ILD (odds ratio, 6.29; 95% CI, 2.34-16.92; P < .001), and ground glass attenuation in interstitial lung abnormalities was an independently associated risk factor (odds ratio, 4.05; 95% CI, 1.29-12.71; P = .01). In this cohort study, preexisting interstitial lung abnormalities, including ground glass attenuation, were risk factors associated with ICI-ILD in patients with nonlung cancers. This observation is consistent with previously reported findings in patients with lung cancer. Therefore, we should pay more attention to the development of ICI-ILD in patients with interstitial lung abnormalities, regardless of cancer type.

Real-World Outcomes of Patients with Diffuse Large B-Cell Lymphoma Receiving Second Line Therapy in the United States

Background: In the rituximab era, outcome data from patients (pts) receiving second-line therapy (2L) for diffuse large B-cell lymphoma (DLBCL) are derived mostly from randomized controlled trials or selected cohorts from specialized care centers. As new salvage strategies emerge, there is a need to reevaluate the landscape of 2L DLBCL (treatments and outcomes) in real-world (rw) patient cohorts. We investigated the timing of 2L in a cohort of US pts with DLBCL, the utilization of autologous stem cell transplantation (ASCT) as consolidation, and the overall survival (OS) in these pts. Methods We included patients from the Flatiron Health electronic health record (EHR) derived, de-identified database, with a first incident DLBCL diagnosed after January 2011, and with documented 2L therapy receipt (n=524). All pts received ≥4 doses of an anthracycline-based immune-chemotherapy in the frontline therapy (1L) setting and initiated 2L active immune-chemotherapy (anti-CD20 monoclonal antibody monotherapy was excluded) prior to December 2019 to allow for at least 6 m of potential follow-up through May 31 2020. Patients with central nervous system disease at diagnosis were excluded. Real-world overall survival (rwOS) probabilities, indexed to the start of 2L, were estimated in the entire cohort using the Kaplan-Meier method. Hazard ratios (HR) comparing rwOS were estimated using Cox regression models. Baseline covariates included demographic information, DLBCL histologic subtypes, cell of origin (COO) classified by the Hans' algorithm, cytogenetics, and the time interval in months (m) from end of 1L therapy to initiation of 2L therapy. Analyses were also re-indexed to 1 and 3 years post-2L, comparing unadjusted rwOS in pts who had received ASCT on or prior to these timepoints versus those who did not. Results In the study sample of 524 pts (57% men), median age at 2L initiation was 68 years (range 59 to 76) and 63% had stage III or IV disease at diagnosis. Initiation of 2L happened within 6 m of 1L completion for a majority of pts, 276/524 (53%), and within 2 months for one quarter, 137/524 (26%); for the rest, 92 pts (18%) initiated between 6-&amp;lt;12 m after 1L completion, 72 pts (14%) between ⩾12-24 m and 84 pts (16%) after 24 m. Consolidation with ASCT was documented for 115 pts (22%) and 17 pts (3%) received chimeric antigen receptor T-cells therapy. Unadjusted median rwOS in the entire cohort was 22 m [95% CI: 17, 38] (Figure 1A). This varied by interval between 1L completion and 2L initiation; for pts with shorter interval (&amp;lt;12 m) from 1L, median rwOS was 17 m [95% CI: 12, 30], while it was 43 m [95% CI: 22, 54] for those with a ⩾12 m interval (Figure 1B). The presence of MYC translocation alone or in combination with other cytogenetic abnormalities was associated with a shorter unadjusted median rwOS vs. absence of MYC: 9.3 m [95% CI: 8.2, 32, n=33] vs. 26 m [95% CI: 18, 43, n=491] (Figure 1C). In the adjusted model controlling for baseline covariates, older age (⩾ 70) appears to be associated with increased hazard of death (HR: 1.48 [95% CI: 1.14, 1.91]). Unadjusted rwOS analyses at 1 year following start of 2L showed better survival for patients receiving ASCT versus those who did not (HR: 0.40 [0.21, 0.76]). This association was sustained at 3 years (HR: 0.17 [0.04, 0.75]. Conclusion In a contemporary cohort of rw pts with DLBCL receiving 2L immune-chemotherapy, the majority did not receive ASCT. In this setting, age ⩾70, shorter intervals between 1L completion and 2L initiation, presence of MYC translocations, and no ASCT were factors associated with shorter survival. It may be important to address the implications of these clinical features in the investigation of 2L therapy options for pts with DLBCL. Disclosures Sawas: Daiichi Sankyo: Speakers Bureau; Affimed: Research Funding; Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau. Lau:Flatiron Health, Inc: Current Employment; Roche: Current equity holder in publicly-traded company. Thomson:Flatiron Health, Inc: Current Employment; Roche: Current equity holder in publicly-traded company. Maignan:Flatiron Health, Inc: Current Employment, Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company.

Stromal reaction inhibitor and immune-checkpoint inhibitor combination therapy attenuates excluded-type colorectal cancer in a mouse model.

Despite recent advances in cancer immunotherapy, the efficacy of colorectal cancer (CRC) immunotherapy regimens is limited. This study evaluated the combined effect of an anti-PD-1 antibody and a platelet-derived growth factor receptor inhibitor (imatinib) on CRC progression using an orthotopic transplanted mouse model that reproduced the three histological phenotypes of CRC (inflamed-, excluded-, and desert-type). The frequency of each of these phenotypes in 196 human CRC tissue samples was also evaluated. Excluded-type CRC had the highest frequency in human tissue samples. In the mouse model, imatinib suppressed stromal reaction and increased sensitivity to anti-PD-1 treatment in excluded-type CRC. Antitumor effect was observed in mice with excluded-type tumors only after concomitant administration of anti-PD-1 antibody and imatinib. Immunohistological analysis revealed a reduction in stromal volume and an increase in the number of CD8-positive T cells in the tumor nest following combination therapy. RNA sequencing revealed significant activation of immune-related pathways and suppression of stromal-related pathways in transplanted tumors treated with combination therapy compared with tumors treated with anti-PD-1 antibody monotherapy. This combination therapy may prove effective for CRC cases that are unresponsive to anti-PD-1 antibody monotherapy.

Combination of rAd-p53 in situ gene therapy and anti-PD-1 antibody immunotherapy induced anti-tumor activity in mouse syngeneic urogenital cancer models

In this study we undertook a novel combination therapy using rAd-p53 in situ gene therapy and immunotherapy with immune checkpoint inhibitor (ICI) anti-PD-1 antibody for urogenital cancers. Three mouse syngeneic tumor cell lines, TRAMP-C2 (prostate cancer derived from C57BL/6 mice), MBT-2 (bladder cancer derived from C3H mice) and Renca (kidney cancer derived from BALB/c mice) were used in this study. The highest coxsackie and adenovirus receptor (CAR) mRNA expression was observed in TRAMP-C2 cells, followed by Renca and then MBT-2 cells. Consistent with the CAR expressions, rAd-p53 at 160 multiplicity of infection (MOI) significantly inhibited the cell proliferation of TRAMP-C2 and Renca cells, but not MBT-2 cells. In in vivo experiments, the combination of intratumoral injections of rAd-p53 (1 × 109 plaque-forming units) every other day and intraperitoneal injections of anti-mouse PD-1 antibody (200 μg) twice a week suppressed tumor growth and prolonged survival compared to rAd-p53 or anti-PD-1 antibody monotherapy in both the TRAMP-C2 and Renca models. Our results encourage the clinical development of combination therapy comprised of in situ gene therapy with rAd-p53 and immunotherapy with an ICI anti-PD-1 antibody for urogenital cancers.

Daratumumab Monotherapy in Severe Patients with AL Amyloidosis and Biopsy-Proven Renal Involvement: A Real Life Experience.

Objectives: This paper aims to describe the clinical experience with Daratumumab (DARA), a first-in-class anti-CD38 human monoclonal IgG1κ antibody monotherapy, in severe patients with AL and biopsy-proven renal involvement. Immunoglobulin light chain (AL) amyloidosis with multi-organ involvement is characterized by short survival. Novel powerful drugs are expanding the therapeutic options. Current treatment of AL amyloidosis, which has been adopted from multiple myeloma (MM), is based on chemotherapy targeting the underlying plasma cell clone. DARA is effective in treating MM. The clinical activity and toxicity profile of DARA as a single agent in the treatment of AL amyloidosis is currently under evaluation. Patients and Methods: DARA was administered in a series of patients with severe AL amyloidosis and biopsy-proven renal involvement. Five patients(mean age 64.2 years) were treated. One patient was refractory and one intolerant to conventional bortezomib-based therapy, two were treated with DARA for relapsing disease, and one was treated front-line. Results: Data showed that DARA monotherapy resulted in good clinical results, with the disappearance of M-proteins in four out of five patients and with serum free light chains (sFLC) ratio normalization in three out of four and a remarkable amelioration in the remaining patient. The four patients with still preserved renal function at baseline also showed serum creatinine stabilization or improvement and a decrease in proteinuria. These data were paralleled by the reduction of the N-terminal prohormone of brain natriuretic peptide (NT pro-BNP)values. Conclusions: Our data show that monotherapy with DARA had significant clinical efficacy in pretreated/naïve patients with severe AL amyloidosis and biopsy-proven renal involvement.

ANTI-HER2 ANTIBODIES IN COMBINATION WITH CHEMOTHERAPY OR CHEMOTHERAPY-FREE REGIMENS TARGETING HER2-POSITIVE BREAST CANCER: A SYSTEMATIC REVIEW

Breast cancer is the leading cause of cancer-related death in female worldwide. Human epidermal growth factor receptor 2 (HER2) amplification is observed in approximately 20% of breast cancer cases and is associated with poor clinical outcomes. Dual HER2 blockade without chemotherapy represents an attractive therapeutic approach, and it remains unresolved if anti-HER2 therapeutic antibodies are sufficient to replace chemotherapy regimens. In this review, we discuss the approved therapeutic monoclonal antibodies (pertuzumab and trastuzumab) and antibody-drug conjugate (trastuzumab emtansine or T-DM1) for the treatment of HER2-positive breast cancer patients. In summary, phase II and III clinical trials have demonstrated that dual HER2 blockade (pertuzumab and trastuzumab) plus chemotherapy regimens confer better efficacy compared with dual HER2 blockade alone, or anti-HER2 antibody monotherapy, in HER2-positive breast cancer patients. Dual HER2 blockade (pertuzumab and trastuzumab) combined with chemotherapies (5-fluorouracil, epirubicin, cyclophosphamide and docetaxel) yield superior response. Moreover, dual HER2 blockade (T-DM1 and pertuzumab) in combination with docetaxel represents a promising treatment regimen containing T-DM1. Ongoing clinical trials are assessing the optimal chemotherapy of choice with anti-HER2 antibodies combinations. In conclusion, improved outcomes are attributable to selection for the optimal chemotherapy regimen in combination with anti-HER2 antibodies instead of replacing chemotherapy altogether with the current line of anti-HER2 therapeutic antibodies.

The Impact of Liver Metastasis on Anti-PD-1 Monoclonal Antibody Monotherapy in Advanced Melanoma: Analysis of Five Clinical Studies.

Anti-programmed cell death protein 1 (PD-1) monoclonal antibody therapy is becoming a standard treatment for advanced melanoma that produces durable responses and prolonged survival, but the prognosis of patients with liver metastases is still unsatisfactory. Here, we analyzed five clinical studies (second-line or later, JS001-I-PK, CT4, KN151, BGB-A317-102, and SHR-1210-102; performed between 2015 and 2018) of anti-PD-1 monotherapy for advanced melanoma to explore prognostic variables for patients with liver metastases. A total of 168 patients with stage IV melanoma were included, among which 47 had liver metastasis and 121 did not. The objective response rate (ORR) of the no liver metastasis group was significantly higher than that of the liver metastasis group (20.7 vs. 4.3%, P < 0.05). The median progression-free survival (PFS) time was 3.6 months for the patients with liver metastasis and 7.4 months for those without liver metastasis (P < 0.05). The no liver metastasis group also had a longer median overall survival (OS) time than the liver metastasis group (22.8 vs. 15.7 months, P < 0.05). Multivariate analysis showed that liver metastasis was negatively associated with PFS. In the liver metastasis group, compared to metastases in other sites (lymph node, subcutaneous, and lung), liver metastases responded worse to anti-PD-1 monotherapy and were most likely to progress. Intrahepatic progression (defined as an increase in liver metastasis by more than 20% from baseline or having new liver metastases, P < 0.05) was negatively associated with OS, which indicates the need to find a more effective therapy that can target liver metastases. Interestingly, with a median PFS and OS time of 6.0 and 30.9 months, respectively, previous oncolytic virotherapy might bring more benefits to patients with liver metastasis, but confirmation is needed because of the limited number of samples. These findings emphasize that liver metastasis is a poor prognostic factor for advanced melanoma treated with anti-PD-1 monotherapy. Further exploration is still needed to find a new treatment approach for these patients.

1153TiP A phase II, open label study to investigate the efficacy and safety of domatinostat in combination with avelumab in patients with advanced unresectable/metastatic Merkel cell carcinoma progressing on anti-PD-(L)1 antibody therapy: The MERKLIN 2 study

Merkel cell carcinoma (MCC) is a rare but highly aggressive human skin cancer that is often caused by the Merkel cell polyomavirus or extended exposure to sunlight. Historically, first-line treatment options for patients with advanced unresectable/metastatic MCC have been rare. However, since the approvals of avelumab globally and subsequently pembrolizumab (US only), anti-PD-(L)1 antibody therapies have become standard of care for MCC patients in recent years. Despite these successes, a significant proportion of MCC patients do not respond or relapse to previous anti-PD-(L)1 antibody monotherapy ultimately leaving these patients with only limited treatment options.

Development of nomograms to predict therapeutic response and prognosis of non-small cell lung cancer patients treated with anti-PD-1 antibody.

Anti-programmed death-1 (PD-1) antibody changed the treatment of non-small cell lung cancer (NSCLC), however, reliable predictive markers were lacking. We aimed to explore factors associated with response and survival, and develop predictive models. This multicenter retrospective study included a training cohort (n = 92) and validation cohort (n = 111) with NSCLC patients received anti-PD-1 antibody monotherapy in eight Chinese hospitals, and a control cohort (n = 124) with NSCLC patients received chemotherapy. Logistic and Cox models were used to identify factors associated with response and survival respectively. Nomograms were developed based on significant factors, and evaluated by Concordance-index (C-index), area under the curve (AUC) and calibration curve. In training cohort, smoking history (P = 0.027) and higher absolute lymphocyte count (P = 0.038) were associated with response. Female (P < 0.001), age ≥ 65years (P = 0.004) and higher lactate dehydrogenase (LDH, P < 0.001) were associated with shorter progression-free survival (PFS). Higher LDH (P < 0.001) and derived neutrophil-to-lymphocyte ratio (P = 0.035) were associated with poorer overall survival (OS). While these factors were nonsignificant in chemotherapy cohort. Three nomograms to predict response at 6-week after treatment, PFS and OS at 6-, 12- and 18-months were developed, and validated in validation cohort. The C-indices of each nomogram in both cohorts were as follow (training vs validation): 0.706 vs 0.701; 0.728 vs 0.701; 0.741 vs 0.709; respectively. AUC showed a good discriminative ability. Calibration curves demonstrated a consistence between actual results and predictions. We developed predictive nomograms based on easily available factors to help clinicians early assess response and prognosis for NSCLC patients received anti-PD-1 antibody.

Abstract 5531: K0401-020 anti-VISTA antibody monotherapy increases specific CD8 T cell response in non-human primates

Abstract Background: VISTA is a B7 family protein described as a negative checkpoint of T cell responses, both in autoimmunity and cancer murine models. K01401-020 is a novel IND enabling anti-VISTA antibody. In vitro, when incubated with human blood cells, K01401-020 stimulates NK cells, monocytes and cytokine production, contributing to T cell activation. In vivo, in non-human primates, K01401-020 notably induced dendritic cell activation (Loukili et al, AACR 2019). However, so far, no in vivo demonstration of anti-VISTA pharmacodynamic effect on T cells has been demonstrated beyond mouse models. Thus, we explored the effect of anti-VISTA antibody on CD8 T cell specific activation in non-human primates, using SIV immunization as a model. Methods: The detection of T cell response amplification by immune-checkpoint inhibitors is very challenging in primates during standard PK or safety studies in the absence of adequate antigen stimulation. KLH is described as an immunogen in monkeys but induces mainly a humoral (IgG/IgM) and not a CD8 response, and thus cannot reveal the pharmacodynamic activity of immune-checkpoint inhibitors. Here, we explored well-described model of primate immunization that induces specifically a cellular response including CD8 (Martinon et al, Hum Gene Ther. 2009) to reveal the activity of Immune-checkpoints inhibitors. Groups of three adult cynomolgus macaques were immunized thrice with 1mg of MultiSIVmac239 GTU-DNA, by intradermal route with electroporation. One-day after the last immunization, animals received a single intravenous injection of either vehicle, anti-PD1 antibody (pembrolizumab) or anti-VISTA antibody K01401-020. IFNγ ELISPOT assay was performed on PBMCs in the presence of either Nef RM9 peptide or Gag (peptide pool), while RM9 tetramer assay and cell subsets phenotyping were performed on whole blood. Results: RM9 and gag-specific CD8 responses were evidenced as soon as after the second immunization in at least 2/3 animals from all groups. The third immunization reactivated CD8-specific responses in all groups. Pembrolizumab and anti-VISTA antibody clearly amplified CD8 specific responses respectively in 2/3 and 3/3 monkeys. Conclusions: Here we show for the first time that a single anti-VISTA antibody infusion monotherapy in non-human primates potentializes specific CD8 T cell responses against exogenous antigen. The above data suggests that anti-VISTA antibody K01401-020 given as a single agent may effectively boosts CD8 T cell activity against tumor antigens. Confidential – Pierre Fabre and CEA collaboration Citation Format: Christine Libon, Isabelle Vandenberghe, Romain Marlin, Wesley Gros, Marco Leonec, Mario Gomez-Pacheco, Anne-Sophie Gallouet, Françoise Fraboul, Abderrahim Mahfoudi, Nathalie Dereuddre-Bosquet, Pierre Ferré. K0401-020 anti-VISTA antibody monotherapy increases specific CD8 T cell response in non-human primates [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5531.

Poor efficacy of anti-programmed cell death-1/ligand 1 monotherapy for non-small cell lung cancer patients with active brain metastases.

BackgroundThe efficacy of anti‐programmed cell death‐1/ligand 1 antibody monotherapy (anti‐PD‐1/PD‐L1 monotherapy) in patients with active brain metastases (BMs) is not established. Here, we aimed to evaluate the efficacy of anti‐PD‐1/PD‐L1 monotherapy in non‐small cell lung cancer (NSCLC) patients with active BMs.MethodsThis retrospective study included NSCLC patients treated with second‐line or later‐line anti‐PD‐1/PD‐L1 monotherapy between December 2015 and August 2019. Patients were classified into those with or without active BMs, including symptomatic BMs requiring systemic steroids and untreated BMs. The progression‐free survival (PFS) and overall survival (OS) of the patients with and without active BMs were compared. Intracranial and extracranial tumor responses were evaluated in patients with active BMs.ResultsWe analyzed 197 patients who had received anti‐PD‐1/PD‐L1 monotherapy. Among them, 24 had active BMs. Among those without active BMs, 145 had no BMs and 28 had treated asymptomatic BMs. The PFS and OS of patients with active BMs were significantly shorter than those of patients without active BMs (1.3 vs. 2.7 months; P < 0.001, and 4.5 vs. 16.3 months; P = 0.001 respectively). For patients with active BMs, the intracranial and extracranial response rates were 13.3% and 26.7%, respectively. On multivariate analysis, active BMs, poor performance status (PS), and EGFR/ALK positivity were significant factors associated with shorter PFS. Active BMs and poor PS were significant factors associated with shorter OS.ConclusionsThis study suggested that anti‐PD‐1/PD‐L1 monotherapy was not effective for NSCLC patients with active BMs. Further studies on immunotherapy are needed for patients with active BMs.Key pointsSignificant findings of the study: The present study showed that anti‐PD‐1/PD‐L1 antibody monotherapy was not effective for non‐small cell lung cancer patients with active brain metastases. Intracranial and extracranial response rates were 13.3% and 26.7%, respectively.What this study adds: Further studies on immunotherapy are needed for patients with active BMs.