This phase II study tested granulocyte-macrophage colony-stimulating factor (GM-CSF)-allogeneic pancreatic tumor cells (GVAX) and ipilimumab in metastatic pancreatic ductal adenocarcinoma (PDA) in ...the maintenance setting.
Patients with PDA who were treated with front-line chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the metastatic setting and had ongoing response or stable disease after 8-12 doses were eligible. Patients were randomized 1:1 to treatment with GVAX and ipilimumab given every 3 weeks for four doses then every 8 weeks (Arm A) or to FOLFIRINOX continuation (Arm B). The primary objective was to compare overall survival (OS) between the two arms.
Eighty-two patients were included in the final analysis (Arm A: 40; Arm B: 42). The study was stopped for futility after interim analysis. Median OS was 9.38 months 95% confidence interval (CI), 5.0-12.2 for Arm A and 14.7 months (95% CI, 11.6-20.0) for Arm B (HR, 1.75;
= 0.019). Using immune-related response criteria, two partial responses (5.7%) were observed in Arm A and four (13.8%) in Arm B. GVAX + ipilimumab promoted T-cell differentiation into effector memory phenotypes both in the periphery and in the tumor microenvironment and increased M1 macrophages in the tumor.
GVAX and ipilimumab maintenance therapy did not improve OS over continuation of chemotherapy and resulted in a numerically inferior survival in metastatic PDA. However, clinical responses and biological effects on immune cells were observed. Further study of novel combinations in the maintenance treatment of metastatic PDA is feasible.
Ascorbate (vitamin C) has been evaluated as a potential treatment for cancer as an independent agent and in combination with standard chemotherapies. This review assesses the evidence for safety and ...clinical effectiveness of intravenous (IV) ascorbate in treating various types of cancer.
Single arm and randomized Phase I/II trials were included in this review. The PubMed, MEDLINE, and Cochrane databases were searched. Results were screened by three of the authors (GN, RP, and CJP) to determine if they met inclusion criteria, and then summarized using a narrative approach.
A total of 23 trials involving 385 patients met the inclusion criteria. Only one trial, in ovarian cancer, randomized patients to receive vitamin C or standard of care (chemotherapy). That trial reported an 8.75 month increase in progression-free survival (PFS) and an improved trend in overall survival (OS) in the vitamin C treated arm.
Overall, vitamin C has been shown to be safe in nearly all patient populations, alone and in combination with chemotherapies. The promising results support the need for randomized placebo-controlled trials such as the ongoing placebo-controlled trials of vitamin C and chemotherapy in prostate cancer.
A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients ...with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.
Differentiated thyroid cancer (DTC) responds to VEGF receptor inhibitors. VEGF signals through RAS/RAF/MEK signaling. We evaluated the safety and efficacy of the VEGF receptor inhibitor pazopanib and ...MEK inhibitor trametinib in advanced solid tumors and DTC.
Patients with advanced solid tumors were enrolled in a phase I, multicenter trial with a DTC expansion cohort. Patients received pazopanib 400-800 mg and trametinib 1-2 mg daily. Efficacy in the expansion cohort was assessed with objective response (OR) at 6 months of treatment.
Twenty-six patients were enrolled in five dose levels. MTD was not reached; the recommended phase II dose was pazopanib 800 mg orally and trametinib 2 mg orally every day. There was one dose-limiting toxicity on dose level 1 with grade 3 fatigue and muscle weakness. Common grade 3 adverse events were elevated transaminases (19%), diarrhea (15%), hypertension (12%), and fatigue (8%). Thirteen patients were enrolled in the DTC cohort; OR was 33% (95% confidence interval, 9.9, 65.1%) and median progression-free survival was 10.7 months. The cohort was terminated after planned interim analysis suggested insufficiently increased activity against the historical control of pazopanib alone. Reduction in tumor diameter negatively correlated with p-ERK change in tumor (Spearman ρ = -0.71;
= 0.05).
mutation was associated with response (Fisher exact
= 0.008).
Pazopanib + trametinib was tolerable at full single-agent doses with clinical activity in DTC but did not achieve the prespecified response rate target.
The transcription factor Early Growth Response 3 (Egr3) has been shown to play an important role in negatively regulating T cell activation and promoting T cell anergy in Th1 cells. However, its role ...in regulating other T helper subsets has yet to be described. We sought to determine the role of Egr3 in a Th17 response using transgenic mice that overexpress Egr3 in T cells (Egr3 TG). Splenocytes from Egr3 TG mice demonstrated more robust generation of Th17 cells even under non-Th17 skewing conditions. We found that while Egr3 TG T cells were not intrinsically more likely to become Th17 cells, the environment encountered by these cells was more conducive to Th17 development. Further analysis revealed a considerable increase in the number of γδ T cells in both the peripheral lymphoid organs and mucosal tissues of Egr3 TG mice, a cell type which normally accounts for only a small fraction of peripheral lymphocytes. Consistent with this marked increase in peripheral γδ T cells, thymocytes from Egr3 TG mice also appear biased toward γδ T cell development. Coculture of these Egr3-induced γδ T cells with wildtype CD4+ T cells increases Th17 differentiation, and Egr3 TG mice are more susceptible to bleomycin-induced lung inflammation. Overall our findings strengthen the role for Egr3 in promoting γδ T cell development and show that Egr3-induced γδ T cells are both functional and capable of altering the adaptive immune response in a Th17-biased manner. Our data also demonstrates that the role played by Egr3 in T cell activation and differentiation is more complex than previously thought.
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Approximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical studies have shown that ...combined histone deacetylases (HDAC) and/or DNA methyltransferases (DNMT) inhibition can induce susceptibility to immune checkpoint therapy and inhibit tumor growth. We conducted a pilot trial evaluating PD-1 immune checkpoint inhibitor therapy in combination with DNMT and HDAC inhibitors in MMRp CRC. The study was designed with a biological endpoint of change in immune cell infiltration, to determine the optimal epigenetic combination that optimizes the tumor microenvironment. This trial was designed to test that hypothesis.
From January 2016 to November 2018, 27 patients were enrolled with median age of 57 (range 40-69) years. Median progression-free survival and overall survival were 2.79 months and 9.17, respectively. One patient in Arm C achieved a durable partial response by RECIST criteria, lasting for approximately 19 months. The most common treatment-related hematological adverse events in all arms were anemia (62%), lymphopenia (54%) and thrombocytopenia (35%), and non-hematological AEs were anorexia (65%), nausea (77%), and vomiting (73%).
The combination of 5-azacitidine and romidepsin with pembrolizumab was safe and tolerable in patients with advanced MMRp CRC, but with a minimal activity. Further mechanistic investigations are needed to understand epigenetic-induced immunologic shift and to expand the potential applicability of checkpoint inhibitors in this setting.
The cell-mediated immune profile induced by a recombinant DNA vaccine was assessed in the simian/HIV (SHIV) and macaque model. The vaccine strategy included coimmunization of a DNA-based vaccine ...alone or in combination with an optimized plasmid encoding macaque IL-15 (pmacIL-15). We observed strong induction of vaccine-specific IFN-γ-producing CD8⁺ and CD4⁺ effector T cells in the vaccination groups. Animals were subsequently challenged with 89.6p. The vaccine groups were protected from ongoing infection, and the IL-15 covaccinated group showed a more rapidly controlled infection than the group treated with DNA vaccine alone. Lymphocytes isolated from the group covaccinated with pmacIL-15 had higher cellular proliferative responses than lymphocytes isolated from the macaques that received SHIV DNA alone. Vaccine antigen activation of lymphocytes was also studied for a series of immunological molecules. Although mRNA for IFN-γ was up-regulated after antigen stimulation, the inflammatory molecules IL-8 and MMP-9 were down-regulated. These observed immune profiles are potentially reflective of the ability of the different groups to control SHIV replication. This study demonstrates that an optimized IL-15 immune adjuvant delivered with a DNA vaccine can impact the cellular immune profile in nonhuman primates and lead to enhanced suppression of viral replication.
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BackgroundData analysis of specimens from prior clinical trials identified the immune co-simulatory molecule CD137 within the tumor microenvironment(TME) of pancreatic ductal adenocarcinoma(PDAC) ...that remain to be activated following vaccine induced T cell and PD-1 inhibitory treatments. The requirement of CD137 was subsequently supported by preclinical studies. Therefore, we conducted a clinical trial of combining anti-CD137 agonist antibody urelumab, anti-PD-1 antagonist antibody nivolumab and a GM-CSF-secreting allogeneic tumor cell vaccine(GVAX) as neoadjuvant and adjuvant therapy for resectable PDAC.MethodsPatients of >=18 years old with radiographic evidence of resectable PDACs were eligible for Arm C of this trial(NCT02451982) with an accrual goal of 10 evaluable subjects. The primary objective was to evaluate changes in numbers of tumor infiltrating CD137+CD8+ T cells. Secondary objectives were safety, overall survival, disease free survival, and other immune parameters. Patients who underwent R0/R1 resection were considered evaluable. All subjects received 480mg nivolumab and 8 mg urelumab both intravenously one day prior to receiving GVAX intradermally and two weeks before surgical resection (figure 1). After surgery, eligible patients continued to receive 5 combination immunotherapy cycles in addition to standard of care chemotherapy. Treatment-related toxicity and perioperative complications are monitored.ResultsBetween February 2019 and August 2020, we completed planned enrollment and treated 10 evaluable patients, who underwent R0 surgical resection of their PDACs. Nausea is the most common adverse event attributed to urelumab (table 1). Other adverse events and perioperative complication were observed in a type, frequency and degree similar to other treatment arms. After repeated dosing, 1 patient demonstrated grade 1 arthritis; 1 patient demonstrated self-limited, transient grade 2 elevated LFTs; 1 patient developed grade 3 rashes, which responded quickly to oral steroid and did not recur after re-dosing. Interestingly, two out of 10 resected patients demonstrated CAP grade 2 pathologic responses in the resected PDACs after a single neoadjuvant treatment; this was not observed with other treatment cohorts(GVAX alone or GVAX+nivolumab) in this neoadjuvant platform trial. Nine out of 10 resected patients remain disease free after a median follow up of 12 months. Immunology endpoints are being analyzed by multiplex immunohistochemistry, DNA sequencing for neoantigen loads, and RNA/TCR sequencing.Abstract 812 Figure 1Study SchemaAbstract 812 Table 1Adverse EventsConclusionsPrevious observations of liver toxicity with urelumab or other T cells agonists and severe immune-related adverse events were not observed in this trial, suggesting urelumab(8 mg) is safe as neoadjuvant/adjuvant therapy in this resectable PDAC patient population. Immune and clinical efficacy of anti-CD137 agonist-based combinations warrant further investigation.AcknowledgementsThis is an investigator initiated clinical trial and supported by the funding from the Rare Disease Program at Bristol-Myers Squibb.Trial RegistrationNCT02451982Ethics ApprovalThe study was approved by the Johns Hopkins Medical Institution Institutional Review Board, approved number IRB00050517
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Background: Intraarterial therapies (IAT) are treatment options for selected intrahepatic cholangiocarcinoma (iCCA), with reasonable effectiveness. CCA are abundantly infiltrated with ...macrophages and M2-tumor associated macrophages (TAM) are associated with the risk of metastasis. By binding to colony-stimulating factor 1 receptor (CSF-1R) and blocking activation by its ligands, SNDX-6352 (axatilimab) can affect the migration, differentiation and survival of TAMs. We aimed to investigate the safety and clinical activity of combining IAT plus anti-PDL1 and axatilimab in iCCA (NCT04301778). Methods: This was a phase 2 study for patients with liver-limited, unresectable iCCA. Patients received treatment with either trans-arterial chemo-embolization (cTACE) or radio-embolization (Y90) every 8 weeks. Durvalumab was started one week following the first IAT procedure. Beginning with the second cycle, durvalumab and axatilimab combination therapy was given on Day 1 (both drugs) and Day 15 (axatilimab only) of each 28-day cycle. Patients underwent biopsy at baseline, at weeks 4 (after durvalumab single agent) and at week 8, during the second IAT procedure. Major immune cell subtypes, including T cell and myeloid cell, were characterized by multiplex immunohistochemistry on the formalin-fixed paraffin-embedded tissue slides of these biopsy specimens. T cell exhaustion pathways, including TIGIT expression on T cells and its ligand PVR(CD155) expression on tumor epithelial cells, were examined. Results: The study was closed early due to slow accrual. At the time of data cut of (11/2022), 5 patients were enrolled. The median age was 60 years (range 39-64) and 2/5 were male. Grade 3 treatment-related adverse events were reported by 3 patients including elevated CK and AST in 2 patients, elevated ALT in one patient, femoral pseudoaneurysm and cellulitis in one patient. No grade 4-5 adverse events were observed. One patient had partial responses by RECIST 1.1, and 1 had stable disease. Two patients had partial response of target lesions, but overall progression due to appearance of new liver lesions. PVR was moderately to strongly expressed on tumor epithelial cells and TIGIT+ T cells were abundantly infiltrated in all cases at baseline. PVR expression and TIGIT+ T cell infiltration appeared decreased following durvalumab and axatilimab treatments, although these changes could be secondary to tumor regression. Conclusions: The combination of IAT, durvalumab and axatilimab was generally well tolerated in patients with advanced CCA, with some signal of activity observed. Correlative studies suggest TIGIT axis modulation as a potential target of combination immunotherapy in patients with CCA. Further investigations are needed to expand the applicability of combination of immunotherapy with local therapies in CCA. Clinical trial information: NCT04301778 .
DNA methyltransferase inhibitors (DNMTi) have demonstrated benefit in reversing resistance to systemic therapies for several cancer types. In a phase II trial of guadecitabine and irinotecan compared ...to regorafenib or TAS-102 in pts with advanced mCRC refractory to irinotecan. Patients with mCRC refractory to irinotecan were randomized 2:1 to guadecitabine and irinotecan (Arm A) vs standard of care regorafenib or TAS-102 (Arm B) on a 28-day cycle. Between January 15, 2016 and October 24, 2018, 104 pts were randomized at four international sites, with 96 pts undergoing treatment, 62 in Arm A and 34 in Arm B. Median overall survival was 7.15 months for Arm A and 7.66 months for Arm B (HR 0.93, 95% CI: 0.58-1.47, P = .75). The Kaplan-Meier rates of progression free survival at 4 months were 32% in Arm A and 26% in Arm B. Common ≥Grade 3 treatment related adverse events in Arm A were neutropenia (42%), anemia (18%), diarrhea (11%), compared to Arm B pts with neutropenia (12%), anemia (12%). Guadecitabine and irinotecan had similar OS compared to standard of care TAS-102 or regorafenib, with evidence of target modulation. Clinical trial information: NCT01896856.
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