Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.

Glioblastoma (GBM) is a fast-growing brain tumor that happens in about half of all gliomas. Surgery is the first treatment for patients with newly diagnosed GBM, followed by the usual radiation and chemotherapy pills named temozolomide. Temozolomide pills are then given as a long-term treatment. The outcome for the patient with newly diagnosed GBM remains poor. IGV-001 is specially made for each patient. The tumor cells are removed during surgery and mixed in the laboratory with a small DNA, IMV-001. This mix is the IGV-001 therapy that is designed to give antitumor immunity against GBM. IGV-001 is put into small biodiffusion chambers that are irradiated to stop the growth of any tumor cells in the chambers. In the phase IIb study, patients with newly diagnosed GBM are chosen and assigned to either the IGV-001 or the placebo group. A placebo does not contain any active ingredients. The small biodiffusion chambers containing either IGV-001 or placebo are surgically placed into the belly for 48 to 52 h and then removed. Patients then receive the usual radiation and chemotherapy treatment. Patients must be adults aged between 18 and 70 years. Patients also should be able to care for themselves overall, but may be unable to work or have lower ability to function. Patients with tumors on both sides of the brain are not eligible. The main point of this study is to see if IGV-001 helps patients live longer without making the illness worse compared with placebo. Clinical Trial Registration: NCT04485949 (ClinicalTrials.gov).

Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer.

Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects. Here, we outline ongoing trials and review the rationale and evidence for the combination of avelumab, an anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), with cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 mAb. Avelumab is approved as a monotherapy for the treatment of Merkel cell carcinoma and urothelial carcinoma, and in combination with axitinib for renal cell carcinoma; cetuximab is approved in combination with chemotherapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN) and RAS wild-type metastatic colorectal cancer, and in combination with radiation therapy for SCCHN. Avelumab binds to PD-L1 expressed on tumor cells and immune regulatory cells, thus blocking its interaction with programmed death 1 and reventing T-cell suppression; cetuximab inhibits the EGFR signaling pathway, inhibiting proliferation and inducing apoptosis. Both therapies have complementary mechanisms of action and may also activate the immune system to induce innate effector function through the binding of their Fc regions to natural killer (NK) cells. Furthermore, cetuximab combined with chemotherapy has been shown to induce immunogenic cell death and leads to an increase in tumor-infiltrating CD8+ T and NK cells, which should synergize with the immunostimulatory effects of avelumab. Prospective studies will investigate this combination and inform future treatment strategies.

Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis.

BACKGROUND: Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma. METHODS: Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome. RESULTS: 249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24-43), and median treatment duration was 2.8 months (range 0.5-42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses. CONCLUSIONS: After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.

Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.

BACKGROUND: Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. METHODS: We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0.2 and statistical power of 0.8. This study was registered with ClinicalTrials.gov, number NCT01185964. FINDINGS: 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6.6 months (95% CI 4.1-8.3) with olaratumab plus doxorubicin and 4.1 months (2.8-5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44-1.02, p=0.0615). Median overall survival was 26.5 months (20.9-31.7) with olaratumab plus doxorubicin and 14.7 months (9.2-17.1) with doxorubicin (stratified HR 0.46, 0.30-0.71, p=0.0003). The objective response rate was 18.2% (9.8-29.6) with olaratumab plus doxorubicin and 11.9% (5.3-22.2) with doxorubicin (p=0.3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 µg/mL (geometric coefficient of variation in percentage [CV%] 26.2) to 487 µg/mL (CV% 33.0) and from 123 µg/mL (CV% 31.2) to 156 µg/mL (CV% 38.0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). INTERPRETATION: This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11.8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. FUNDING: Eli Lilly and Company.

The Evolving Role of Immune Checkpoint Inhibitors in Cancer Treatment.

UNLABELLED: Traditional treatment modalities for advanced cancer (radiotherapy, chemotherapy, or targeted agents) act directly on tumors to inhibit or destroy them. Along with surgery, these modalities are predominantly palliative, with toxicity and only modest improvements in survival in patients with advanced solid tumors. Accordingly, long-term survival rates for most patients with advanced cancer remain low, thus there is a need for cancer treatments with favorable benefit and toxicity profiles that can potentially result in long-term survival. The immune system plays a critical role in the recognition and eradication of tumor cells ("immune surveillance"), and immunotherapies based on this concept have been used for decades with some success against a few tumor types; however, most immunotherapies were limited by a lack of either substantial efficacy or specificity, resulting in toxicity. We now have a greater understanding of the complex interactions between the immune system and tumors and have identified key molecules that govern these interactions. This information has revitalized the interest in immunotherapy as an evolving treatment modality using immunotherapeutics designed to overcome the mechanisms exploited by tumors to evade immune destruction. Immunotherapies have potentially complementary mechanisms of action that may allow them to be combined with other immunotherapeutics, chemotherapy, targeted therapy, or other traditional therapies. This review discusses the concepts and data behind immunotherapies, with a focus on the checkpoint inhibitors and their responses, toxicities, and potential for long-term survival, and explores promising single-agent and combination therapies in development. IMPLICATIONS FOR PRACTICE: Immunotherapy is an evolving treatment approach based on the role of the immune system in eradicating cancer. An example of an immunotherapeutic is ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor immune responses. Ipilimumab is approved for advanced melanoma and induced long-term survival in a proportion of patients. The programmed death-1 (PD-1) checkpoint inhibitors are promising immunotherapies with demonstrated sustained antitumor responses in several tumors. Because they harness the patient's own immune system, immunotherapies have the potential to be a powerful weapon against cancer.

Patient responses to ipilimumab, a novel immunopotentiator for metastatic melanoma: how different are these from conventional treatment responses?

Advanced melanoma has defied treatment advances for several decades. Immunotherapy with high-dose interleukin-2 or interferon-α has been beneficial in some cases, but significant toxicities limit its use. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) signaling switches off T-cell activation and induces immune tolerance. Inhibiting CTLA-4 prolongs the antitumor T-cell response, reversing tolerance. Ipilimumab is a first-in-class anti-CTLA-4 monoclonal antibody, currently under review by the Food and Drug Administration for pretreated melanoma. Ipilimumab has shown durable responses and manageable toxicities in a large phase 3 clinical trial in patients with advanced melanoma. Variable response patterns have been observed, including: (1) response in baseline lesions; (2) a slow, steady decline in tumor burden; (3) response after an increase in tumor burden; and (4) response in index and new lesions accompanied by the appearance of other new lesions. Although responses (1) and (2) may be captured using standard methods, atypical responses (3) and (4) would be classified as progressive disease using conventional assessments. Patients on ipilimumab may have delayed responses or durable stable disease even after apparent disease progression, therefore using new immune-related response criteria is recommended to avoid premature treatment withdrawal. This review compares and contrasts responses to ipilimumab with those after chemotherapy, and discusses treatment implications.

Phase I trial of ALT-801, an interleukin-2/T-cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies.

PURPOSE: ALT-801 is a bifunctional fusion protein comprising interleukin-2 (IL-2) linked to a soluble, single-chain T-cell receptor domain that recognizes a peptide epitope (aa264-272) of the human p53 antigen displayed on cancer cells in the context of HLA-A*0201 (p53+/HLA-A*0201). We evaluated the safety, pharmacokinetics, and pharmacodynamics of ALT-801 in p53+/HLA-A*0201 patients with metastatic malignancies. EXPERIMENTAL DESIGN: p53+/HLA-A*0201 patients were treated with ALT-801 on a schedule of four daily 15-minute intravenous infusions, then 10 days rest and four more daily infusions. Cohorts of patients were treated at 0.015, 0.040, and 0.080 mg/kg/dose. RESULTS: Four, 16, and 6 patients were treated at the 0.015, 0.04, and 0.08 mg/kg cohorts, respectively. Two dose-limiting toxicities (a grade 4 transient thrombocytopenia and a myocardial infarction) in the 0.08 mg/kg cohort established the maximum tolerated dose (MTD) at 0.04 mg/kg. Patients treated at the MTD experienced toxicities similar to those associated with high-dose IL-2 but of lesser severity. The serum half-life of ALT-801 was 4 hours and ALT-801 serum recovery was as expected based on the dose administered. ALT-801 treatment induced an increase of serum IFN-γ but not TNF-α. Response assessment showed 10 subjects with stable disease at at least 11 weeks, and in one who had melanoma metastasis, there is an ongoing complete absence of identifiable disease after resection of radiographically identified lesions. CONCLUSION: This first-in-man study defines an ALT-801 regimen that can be administered safely and is associated with immunologic changes of potential antitumor relevance.

Clinical and experimental studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analogue, in heart failure.

Thyroid hormone has unique actions that make it a novel and possibly useful agent for treatment of heart failure. Because of potential adverse effects of thyroid hormone, however, there has been interest in developing analogues with fewer undesirable side effects. Screening of compounds structurally related to levothyroxine identified 3,5-diiodothyropropionic acid (DITPA) as an analogue with inotropic selectivity and low metabolic activity in hypothyroid rats. When DITPA was administered alone or in combination with captopril in rat and rabbit postinfarction models of heart failure, cardiac output was increased and left ventricular end-diastolic pressure (LV EDP) was decreased without increasing heart rate. A pilot clinical study was undertaken to evaluate the safety and efficacy of DITPA. In a dose-ranging study in 7 normal volunteers the drug was well tolerated. A double-blind comparison then was made of DITPA versus placebo in a group of 19 patients with moderately severe heart failure. Patients were randomly assigned to receive either 1.875 mg/kg of DITPA or placebo daily. After 2 weeks the drug was increased to 3.75 mg/kg daily for an additional 2 weeks. In heart failure patients receiving the drug for 4 weeks, cardiac index was increased (p = 0.04) and systemic vascular resistance index was decreased (p = 0.02). Total serum cholesterol (p = 0.013) and triglycerides (p = 0.005) also were decreased significantly. These results indicate that DITPA is well tolerated and could represent a useful new agent for treatment of congestive heart failure.

Pilot studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analog, in the treatment of congestive heart failure.

After an initial safety study in 7 normal volunteers, a randomized double-blind comparison was made between 3,5-diiodothyropropionic acid (DITPA) and placebo in 19 patients with moderately severe congestive failure. In heart failure patients receiving the drug for 4 weeks, cardiac index was increased (p = 0.04) and systemic vascular resistance index was decreased (p = 0.02). Systolic cardiac function was unchanged but isovolumetric relaxation time was decreased significantly, suggesting improvement in diastolic function. Total serum cholesterol (p = 0.005) and triglycerides (p = 0.01) also were decreased significantly. DITPA could represent a useful new agent for treatment of congestive heart failure.