The Society for Immunotherapy of Cancer perspective on regulation of interleukin-6 signaling in COVID-19-related systemic inflammatory response

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as ‘cytokine storm’. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19

Integrated Assessment of Circulating Cell-Free MicroRNA Signatures in Plasma of Patients with Melanoma Brain Metastasis.

Primary cutaneous melanoma frequently metastasizes to distant organs including the brain. Identification of cell-free microRNAs (cfmiRs) found in the blood can be used as potential body fluid biomarkers for detecting and monitoring patients with melanoma brain metastasis (MBM). In this pilot study, we initially aimed to identify cfmiRs in the blood of MBM patients. Normal donors plasma (healthy, n = 48) and pre-operative MBM patients\u27 plasma samples (n = 36) were compared for differences in \u3e2000 microRNAs (miRs) using a next generation sequencing (NGS) probe-based assay. A 74 cfmiR signature was identified in an initial cohort of MBM plasma samples and then verified in a second cohort of MBM plasma samples (n = 24). Of these, only 58 cfmiRs were also detected in MBM tissues (n = 24). CfmiR signatures were also found in patients who have lung and breast cancer brain metastasis (n = 13) and glioblastomas (n = 36) compared to MBM plasma samples. The 74 cfmiR signature and the latter cfmiR signatures were then compared. We found a 6 cfmiR signature that was commonly upregulated in MBM plasma samples in all of the comparisons, and a 29 cfmiR signature that distinguishes MBM patients from normal donors\u27 samples. In addition, we assessed for cfmiRs in plasma (n = 20) and urine (n = 14) samples collected from metastatic melanoma patients receiving checkpoint inhibitor immunotherapy (CII). Pre- and post-treatment samples showed consistent changes in cfmiRs. Analysis of pre- and post-treatment plasma samples showed 8 differentially expressed (DE) cfmiRs that overlapped with the 35 cfmiR signature found in MBM patients. In paired pre-treatment plasma and urine samples receiving CII 8 cfmiRs overlapped. This study identified specific cfmiRs in MBM plasma samples that may potentially allow for assessment of melanoma patients developing MBM. The cfmiR signatures identified in both blood and urine may have potential utility to assess CII responses after further validation

Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States: An Expanded Access Program.

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%-16.8%) in the treated population (n=947) and 22.1% (95% confidence interval, 18.8%-25.5%) in patients who had ≥1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced ≥1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced ≥1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma

778 Botensilimab, a novel innate/adaptive immune activator, plus or minus balstilimab (anti-PD-1) in “cold” and I-O refractory metastatic solid tumors

Background Botensilimab (BOT) promotes optimized T cell priming, activation and memory formation by strengthening antigen presenting cell/T cell co-engagement. As an Fc-enhanced next-generation anti-CTLA-4 antibody, BOT also promotes intratumoral Treg depletion and reduces complement fixation. We present results from patients with metastatic solid tumors treated with BOT±balstilimab (BAL; anti-PD-1) in an expanded phase IA/B study; NCT03860272. Methods Patients received either BOT monotherapy at 0.1-3 mg/kg every 3 weeks (Q3W), BOT monotherapy 1 or 2mg/kg every 6 weeks (Q6W), BOT 0.1-2mg/kg Q6W+BAL 3 mg/kg every 2 weeks, or a fixed-dose of BOT 150mg Q6W+BAL 450mg Q3W. Unconfirmed responses are included. Of the 44 BOT monotherapy patients, 13 crossed over to combination. Results 142 patients (98 combination, 44 monotherapy [13 crossover]) were evaluable for efficacy/safety (treated as of April 7, 2022 with ≥1 Q6W tumor-imaging assessment). Patients had immunologically cold and/or immunotherapy resistant tumors and were heavily pretreated: 61% received ≥3 prior lines of therapy including 34% prior immunotherapy. Median follow-up was 6.1 months. Disease-specific combination therapy cohorts are being expanded with BOT at 1 or 2mg/kg or 150mg+BAL (including 4 crossover patients): (1) microsatellite stable (MSS) colorectal cancer (n=44, ORR 25%), (2) platinum resistant ovarian cancer (n=18, ORR 28%), (3) sarcoma (n=12, ORR 42%, and (4) PD-(L)1 relapsed/refractory non-small cell lung cancer (n=3, ORR 67%). The ORR was 22% (22/98; 3 CR/19 PR) with median duration of response [DOR] not reached (range,1.4+ to 19.5+ months) in all combination patients (BAL+BOT 0.1-2 mg/kg or 150 mg); 13/22 responses are ongoing. In addition, 15% (2/13) monotherapy patients achieved PR after crossing over to combination therapy. The ORR was 11% (5/44; 1 CR/4 PR) in all monotherapy patients (BOT 0.1-3 mg/kg). Responses were independent of PD-L1 expression and tumor mutation burden. Further evaluation of biomarkers is ongoing including paired biopsies (before/during treatment). Grade 1/2, 3 or 4 treatment-related adverse events (TRAE) occurred in 88%, 29%, 2% respectively. Diarrhea/colitis (19%) was the only grade 3/4 TRAE occurring in ≥5% of patients. There were no cases of hypophysitis or myocarditis. Pneumonitis occurred in 4 patients (3%). Two patients had grade 5 TRAEs (enterocolitis, colonic perforation). Conclusions BOT±BAL demonstrates remarkable activity in heavily pretreated patients with solid tumors historically unresponsive to immunotherapy. The safety profile is consistent with the mechanism of action of BOT. Randomized studies in MSS CRC, pancreatic cancer, and melanoma are planned to open this year. Trial Registration NCT0386027

Standard-Dose Pembrolizumab Plus Alternate-Dose Ipilimumab in Advanced Melanoma: KEYNOTE-029 Cohort 1C, a Phase 2 Randomized Study of Two Dosing Schedules.

PURPOSE: Standard-dose pembrolizumab plus alternative-dose ipilimumab (1 mg/kg Q3W for 4 doses) was tolerable and had robust antitumor activity in advanced melanoma in cohort B of the phase 1 KEYNOTE-029 study. Cohort C evaluated standard-dose pembrolizumab with two other alternative ipilimumab regimens. EXPERIMENTAL DESIGN: Patients with treatment-naive unresectable stage III/IV melanoma were randomly assigned 1:1 to pembrolizumab 200 mg Q3W for {less than or equal to}24 months plus ipilimumab 50 mg Q6W for 4 doses (PEM200+IPI50), or the same pembrolizumab regimen plus ipilimumab 100 mg Q12W for 4 doses (PEM200+IPI100). Primary end points were incidence of grade 3-5 treatment-related adverse events (TRAEs) and objective response rate (ORR) per RECIST v1.1 by independent central review. Per protocol-defined thresholds, grade 3-5 TRAE incidence {less than or equal to}26% indicated meaningful toxicity reduction and ORR {greater than or equal to}48% indicated no decrease in efficacy versus data reported for other PD-1 inhibitor/ipilimumab combinations. RESULTS: Median follow-up on February 18, 2019, was 16.3 months in PEM200+IPI50 ( CONCLUSIONS: Pembrolizumab 200 mg Q3W plus ipilimumab 50 mg Q6W or 100 mg Q12W demonstrated antitumor activity above the predefined threshold; pembrolizumab plus ipilimumab 50 mg Q6W had lower incidence of grade 3-5 TRAEs than the predefined threshold, suggesting a reduction in toxicity

Prospective Molecular Profiling of Circulating Tumor Cells from Patients with Melanoma Receiving Combinatorial Immunotherapy.

BACKGROUND: Blood molecular profiling of circulating tumor cells (CTCs) can enable monitoring of patients with metastatic melanoma during checkpoint inhibitor immunotherapy (CII) and in combination with targeted therapies. We developed a microfluidics-based CTC platform to explore CTC profiling utility in CII-treated patients with melanoma using a melanoma messenger RNA (mRNA)/DNA biomarker panel. METHODS: Blood samples (n = 213) were collected prospectively from 75 American Joint Committee on Cancer-staged III/IV melanoma patients during CII treatment and those enriched for CTCs. CTC profiling was performed using 5 known melanoma mRNA biomarkers and BRAF V600E DNA mutation. CTC biomarker status associations with clinical outcomes were assessed. RESULTS: CTCs were detected in 88% of blood samples from patients with melanoma. CTC-derived biomarkers and clinical variables analyzed using classification and regression tree analysis revealed that a combination of lactate dehydrogenase, CTC-mRNA biomarkers, and tumor BRAF-mutation status was indicative of clinical outcomes for patients with stage IV melanoma (n = 52). The panel stratified low-risk and high-risk patients, whereby the latter had poor disease-free ( CONCLUSIONS: CTC-derived mRNA/DNA biomarkers have utility for monitoring CII, targeted, and combinatorial therapies in metastatic melanoma patients