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In ovarian cancer (OC), IL-17-producing T cells (Th17s) predict improved survival, whereas regulatory T cells predict poorer survival. We previously developed a vaccine whereby patient-derived dendritic cells (DCs) are programmed to induce Th17 responses to the OC antigen folate receptor alpha (FRα). Here we report the results of a single-arm open-label phase I clinical trial designed to determine vaccine safety and tolerability (primary outcomes) and recurrence-free survival (secondary outcome). Immunogenicity is also evaluated. Recruitment is complete with a total of 19 Stage IIIC-IV OC patients in first remission after conventional therapy. DCs are generated using our Th17-inducing protocol and are pulsed with HLA class II epitopes from FRα. Mature antigen-loaded DCs are injected intradermally. All patients have completed study-related interventions. No grade 3 or higher adverse events are seen. Vaccination results in the development of Th1, Th17, and antibody responses to FRα in the majority of patients. Th1 and antibody responses are associated with prolonged recurrence-free survival. Antibody-dependent cell-mediated cytotoxic activity against FRα is also associated with prolonged RFS. Of 18 patients evaluable for efficacy, 39% (7/18) remain recurrence-free at the time of data censoring, with a median follow-up of 49.2 months. Thus, vaccination with Th17-inducing FRα-loaded DCs is safe, induces antigen-specific immunity, and is associated with prolonged remission. The folate receptor alpha (FRα) is overexpressed in the majority of high-grade serous ovarian cancers and has been proposed as a candidate vaccine antigen. Here the authors report the safety and immunogenicity of Th17-inducing dendritic cells pulsed with FRα-derived epitopes in an early phase I clinical trial with ovarian cancer patients.

We present an extensive quantum Monte Carlo (QMC) study of a nearest‐neighbor, singlet‐projection model on the pyrochlore lattice that exhibits SO( N ) symmetry and is sign‐problem‐free. We found that, in contrast to the previously studied two‐dimensional (2D) variations of this model that harbor critical points between their ground state phases, the non‐bipartite pyrochlore lattice in three spatial dimensions appears to exhibit a first‐order transition between a magnetically‐ordered (MO) phase and some, as yet uncharacterized, paramagnetic (PM) phase. We also observe that the MO phase survives to a relatively large value of N = 8 and that it is gone for N = 9.

There are no reliable blood biomarkers for monitoring endometrial cancer patients in the current clinical practice. Circulating tumor DNA (ctDNA) is emerging as a promising non-invasive method to measure tumor burden, define prognosis and monitor disease status in many solid cancers. In this pilot study, we investigated if unique tumor-specific DNA junctions can be used to detect ctDNA levels in patients with endometrial cancer. Chromosomal rearrangements in primary tumors of eleven patients with high-grade or advanced stage endometrial cancer were determined by whole-genome Mate-Pair sequencing. Identified unique tumor-specific junctions were evaluated in pre- and six-week post-surgery patient plasma using individualized quantitative polymerase chain reaction (qPCR) assays. The relationship between clinicopathological features and detection of ctDNA was investigated. CtDNA was detected in 60% (6/10) of cases pre-surgery and in 27% (3/11) post-surgery. The detection of ctDNA pre-surgery was consistent with clinical indicators of aggressive disease such as advanced stage (80% - 4/5), lymphatic spread of disease (100% - 3/3), serous histology (80% - 4/5), deep myometrial invasion (100% - 3/3), lympho-vascular space invasion (75% - 3/4). All patients in which ctDNA was detected post-surgically had type II endometrial cancer. This pilot study demonstrates the feasibility of using personalized tumor-specific junction panels for detecting ctDNA in the plasma of endometrial cancer patients. Larger studies and longer follow-up are needed to validate the potential association between pre-surgical ctDNA detection and the presence of cancers with aggressive pathologic tumor characteristics or advanced stage observed in this study.

Both targeted therapies and immunotherapies provide benefit in resected Stage III melanoma. We hypothesized that the combination of targeted and immunotherapy given prior to therapeutic lymph node dissection (TLND) would be tolerable and drive robust pathologic responses. In NeoACTIVATE (NCT03554083), a Phase II trial, patients with clinically evident resectable Stage III melanoma received either 12 weeks of neoadjuvant vemurafenib, cobimetinib, and atezolizumab ( BRAF -mutated, Cohort A, n  = 15), or cobimetinib and atezolizumab ( BRAF -wild-type, Cohort B, n  = 15) followed by TLND and 24 weeks of adjuvant atezolizumab. Here, we report outcomes from the neoadjuvant portion of the trial. Based on intent to treat analysis, pathologic response (≤50% viable tumor) and major pathologic response (complete or near-complete, ≤10% viable tumor) were observed in 86.7% and 66.7% of BRAF -mutated and 53.3% and 33.3% of BRAF -wild-type patients, respectively (primary outcome); these exceeded pre-specified benchmarks of 50% and 30% for major pathologic response. Grade 3 and higher toxicities, primarily dermatologic, occurred in 63% during neoadjuvant treatment (secondary outcome). No surgical delays nor progression to regional unresectability occurred (secondary outcome). Peripheral blood CD8 + T CM cell expansion associated with favorable pathologic responses (exploratory outcome). Immunotherapy with immune checkpoint inhibitors and targeted therapy with BRAF and MEK inhibition have revolutionized the treatment of melanoma. Here the authors report the results of a phase II trial of neoadjuvant cobimetinib (MEK inhibitor) and atezolizumab (anti-PD-L1) with or without the BRAF inhibitor vemurafenib in patients with resectable Stage III melanoma.

Immune checkpoint inhibitors (ICI) are effective for advanced melanoma. However, most develop ICI resistance. Tumor-derived soluble PD-L1 (sPD-L1) and other immunosuppressive factors drive resistance. We hypothesized that therapeutic plasma exchange (TPE) may remove sPD-L1 from circulation and overcome ICI resistance. Patients with metastatic ICI-resistant melanoma and elevated sPD-L1 received radiotherapy to a minority of metastatic lesions, TPE, and ICI re-challenge. Primary endpoints were adverse events and sPD-L1 reduction. Secondary endpoints included overall survival, response, and progression-free survival. Correlative studies included changes in sPD-L1, other immunosuppressive factors, and immune cell phenotypes. Eighteen patients were included. Treatment was well-tolerated, and levels of sPD-L1 were reduced by TPE (mean 78%, p  < 0.0001). Soluble PD-L1 suppression predicted overall survival. The overall response rate was 61% (16.7% complete, 44.4% partial, 22.2% stable, and 16.7% progressing). Changes in peripheral immune cell populations and immunosuppressive factors predicted overall survival. sPD-L1 and other circulating immunoregulatory molecules mediate ICI resistance. TPE can reduce these factors and resensitize ICI-refractory melanoma. Patients with persistent elevation or rapid rebound of sPD-L1 experienced inferior outcomes, suggesting that multiple courses of TPE may be necessary. These findings may apply to other ICI-resistant cancers. Trial registration: NCT04581382, ReCIPE-M1 (Rescuing Cancer Immunotherapy with Plasma Exchange in Melanoma 1). Tumor-derived soluble PD-L1 drives immune checkpoint inhibitor (ICI) resistance and has recently been reported to be removed by therapeutic plasma exchange (TPE). Here, the authors report a phase I clinical trial investigating the combination of radiotherapy, TPE, and ICI rechallenge in patients with ICI-refractory metastatic melanoma with high PD-L1.

Humoral vaccine responses are known to be suboptimal in patients receiving B-cell targeted therapy, and little is known about vaccine induced T-cell immunity in these patients. In this study, we characterized humoral and cellular antigen-specific anti-SARS-CoV2 responses following COVID-19 vaccination in patients with ANCA-associated vasculitis (AAV) receiving anti-CD20 therapy, who were either B-cell depleted, or B-cell recovered at the time of vaccination and in normal control subjects. SARS-CoV-2 anti-spike (S) and anti-nucleocapsid (NC) antibodies were measured using electrochemiluminescence immunoassays, while SARS-CoV-2 specific T-cell responses to S glycoprotein subunits 1 (S1) and 2 (S2) and receptor binding domain peptide pools were measured using interferon-gamma enzyme-linked immunosorbent spot (ELISPOT) assays. In total, 26 recently vaccinated subjects were studied. Despite the lack of a measurable humoral immune response, B-cell depleted patients mounted a similar vaccine induced antigen-specific T-cell response compared to B-cell recovered patients and normal controls. Our data indicate that to assure a humoral response in patients receiving anti-CD20 therapy, SARS-CoV-2 vaccination should ideally be delayed until B-cell recovery (CD-20 positive B-cells > 10/μl). Nevertheless, SARS-CoV-2 vaccination elicits robust, potentially protective cellular immune responses in these subjects. Further research to characterize the durability and protective effect of vaccine-induced anti-SARS-CoV-2 specific T-cell immunity are needed.

Metastatic uveal melanoma (MUM) has a poor prognosis and treatment options are limited. These patients do not typically experience durable responses to immune checkpoint inhibitors (ICIs). Oncolytic viruses (OV) represent a novel approach to immunotherapy for patients with MUM. We developed an OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-β) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNβ-TYRP1), and conducted a Phase 1 clinical trial with a 3 + 3 design in patients with MUM. VSV-IFNβ-TYRP1 was injected into a liver metastasis, then administered on the same day as a single intravenous (IV) infusion. The primary objective was safety. Efficacy was a secondary objective. 12 patients with previously treated MUM were enrolled. Median follow up was 19.1 months. 4 dose levels (DLs) were evaluated. One patient at DL4 experienced dose limiting toxicities (DLTs), including decreased platelet count (grade 3), increased aspartate aminotransferase (AST), and cytokine release syndrome (CRS). 4 patients had stable disease (SD) and 8 patients had progressive disease (PD). Interferon gamma (IFNγ) ELIspot data showed that more patients developed a T cell response to virus encoded TYRP1 at higher DLs, and a subset of patients also had a response to other melanoma antigens, including gp100, suggesting epitope spreading. 3 of the patients who responded to additional melanoma antigens were next treated with ICIs, and 2 of these patients experienced durable responses. Our study found that VSV-IFNβ -TYRP1 can be safely administered via intratumoral (IT) and IV routes in a previously treated population of patients with MUM. Although there were no clear objective radiographic responses to VSV-IFNβ-TYRP1, dose-dependent immunogenicity to TYRP1 and other melanoma antigens was seen.

Immune checkpoint inhibitors (ICIs) have been transformative in the treatment of patients with metastatic melanoma, but primary and secondary resistance to ICI treatment is common. One key mechanism for ICI resistance is the skewing of the immune response from a cytotoxic (Th1) to a chronic inflammatory (Th2) profile. The small molecule ibrutinib is a dual-target agent that inhibits Bruton's Tyrosine Kinase (BTK) and Interleukin-2-inducible T-cell Kinase (ITK), a key regulator of Th2 immunity. Therefore, combining ibrutinib and pembrolizumab could potentially induce an increase in Th1 immune polarity in melanoma patients. We hypothesize that the combination would be well-tolerated and might result in clinical benefit for patients with metastatic melanoma. The primary aim of this phase I study was to evaluate the safety, tolerability, and determine the maximum tolerated dose (MTD) of ibrutinib in combination with pembrolizumab in patients with metastatic melanoma. A 3 + 3 phase I clinical trial was conducted in patients with unresectable Stage III or metastatic melanoma (stage IV) not amenable to local therapy. Pembrolizumab (200 mg/kg every 3 weeks) was combined with ibrutinib, administered orally at the dose assigned at the time of registration (140 mg daily, 280 mg daily, and 420 mg daily). Patients were treated until disease progression, intolerability, or patient decision to discontinue. Blood samples were collected after each cycle of treatment for immunophenotyping and Th1/Th2 polarity assessment based on immune response markers. Between January 31, 2017 and January 9, 2023, 17 patients were enrolled. The MTD of ibrutinib in combination with pembrolizumab was determined to be 420 mg daily. The adverse events leading to discontinuation included: grade 4 ALT and AST increase (1 pt, DL0); grade 4 ALT increase with grade 3 AST increase (1 pt, DL1); and grade 3 hyponatremia, hypoxia, and maculo-papular rash (1 pt, DL1). Three of the 16 patients treated had objective responses (2 partial responses, 1 complete response) lasting over 8 months. The median progression-free survival was 3 months, and median and overall survival was 1.8 years. The combination treatment did not result in consistent increase in Th1 immune polarity. In conclusion, the maximum tolerated dose of ibrutinib in combination with pembrolizumab in patients with advanced or metastatic melanoma was established at 420 mg by mouth once daily. The combination was well-tolerated but did not result in a consistent increase in Th1 immune polarity; further investigation is needed to assess the relative clinical efficacy of this approach. (Funded by Pharmacyclics; ClinicalTrials.gov number: NCT03021460). www.clinicaltrials.gov, identifier NCT03021460.

Circulating tumor DNA (ctDNA) is predictive of recurrence in resected stage III melanoma, yet its role in the neoadjuvant setting for clinical stage III (cSIII) is unclear. Assess the association between ctDNA and outcomes following neoadjuvant immunotherapy (IO) + targeted therapy (TT) in cSIII melanoma. Patients in the NeoACTIVATE study were treated with neoadjuvant IO + TT, underwent lymphadenectomy, and received adjuvant immunotherapy. Patients with ctDNA testing performed at baseline, pre- and post-operation were analyzed. Baseline positron emission tomography-computed tomography volumetrics and surgical, major pathological responses (MPR) were assessed. Thirteen patients had serial ctDNA, 10 (77%) were detectable at baseline, and 9/10 (90%) had ctDNA clearance. Seven (54%) achieved MPR, all with undetectable preoperative ctDNA, yet 3/7 (43%) had disease recurrence. ctDNA and MPR are poor predictors of recurrence following neoadjuvant IO + TT for cSIII melanoma patients. Further studies are warranted to define the role of ctDNA in this setting.

BackgroundOvarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing.MethodsID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies.ResultsTh17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells.ConclusionsThese findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy.