Viral Vectors Expressing Interleukin 2 for Cancer Immunotherapy.

Clinical research priorities in renal cell carcinoma: renal cell carcinoma chemoprevention strategies including target populations, proposed agents, and clinical trial designs--Workgroup No. 6. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC).

Renal cell carcinoma (RCC) is the most common form of kidney cancer. Immunotherapy with interferon-α (IFNα) and interleukin-2 (IL-2) has been the historical therapy of choice for the treatment of locally advanced or metastatic RCC prior to the more recent development of targeted therapies, including sunitinib and bevacizumab (combined with IFNα). Clinically and statistically significant advantages have been shown with both sunitinib and the combination of bevacizumab + IFNα versus IFNα alone in the treatment of advanced or metastatic RCC. The present study evaluated the incremental costs of bevacizumab + IFNα versus sunitinib for the first-line treatment of advanced or metastatic RCC assuming similar efficacy for these treatments. The efficacy profiles of bevacizumab + IFNα or sunitinib alone have been shown (indirectly) to be similar in patients with RCC; indeed, median progression-free survival (PFS) with either treatment is in the 10- to 11-month range. Therefore, a cost-minimization analysis was performed, focusing on direct medical costs only (drugs, administration and management of adverse events). The analysis considered the perspective of the Italian National Health Service (NHS), comparing the cost of bevacizumab (10 mg/kg) plus IFNα (9, 6 or 3 million IU [MIU]) versus sunitinib (50 mg) as first-line therapies for advanced or metastatic clear-cell RCC. The average cost per treated patient (year 2010 values) was assessed for the two treatment options at 11 months (median PFS). Assuming a PFS of 11 months for both treatment options, bevacizumab + IFNα (9 MIU) would be a lower cost strategy (cost savings of €2052 per patient) than sunitinib. This difference arises mainly from the reduction in the acquisition cost of bevacizumab to the NHS (risk-sharing agreement). The cost advantages for bevacizumab would increase in parallel with a reduction in IFNα dosing; for example, with IFNα 6 MIU the corresponding cost savings would be €4185, and with 3 MIU the cost advantage would be €6320 per patient. This analysis suggests that bevacizumab + IFNα is a cost-saving alternative to sunitinib in the treatment of first-line metastatic RCC. Its superior safety profile also meant that the cost of managing adverse events was lower for bevacizumab + IFNα than for sunitinib.

Carrier Cell-based Delivery of an Oncolytic Virus Circumvents Antiviral Immunity

2502 Background: IL-21, a cytokine with homology to IL-2, has demonstrated anti-tumor activity in multiple preclinical tumor models. Methods: In an ongoing phase I dose-escalation study, IL-21 was administered by intravenous push to patients (pts) with AJCC stage 4 metastatic melanoma and renal cell carcinoma. Doses ranging from 3–1000 μg/kg/day x 5 days are planned. Study objectives are to determine a maximally tolerated dose, and to assess pharmacokinetics, immunogenicity, immunomodulatory and anti-tumor activity of IL-21. Results: Patients have been sequentially enrolled in groups of three at dose levels of 3 and 10 μg/kg/day for two 5-day cycles separated by a 9 or 16 day rest interval. All patients experienced one or more adverse events, but no drug-related serious adverse events or CTCAE grade 3 or 4 events have been observed among 6 pts treated {metastatic melanoma (5) and metastatic renal cell carcinoma (1)}. A disease-related grade 3 hemoptysis was observed. Grade 2 adverse events of any relation...

High dose interleukin-2 (IL-2) has been found to produce durable antitumor responses in some patients, benefiting most greatly those patients with melanoma and renal cell carcinoma. In this paper, the hematologic toxicity and changes resulting from high dose IL-2 alone administered by intravenous bolus are discussed. One hundred ninety-nine consecutive patients treated with high dose IL-2 alone from January 1, 1988 to December 31, 1992 were included in this study. All patients had a diagnosis of metastatic melanoma or metastatic renal cell carcinoma and were treated at the National Cancer Institute (Bethesda, MD). Anemia, requiring erythrocyte transfusions, occurred in 14% of all treatment courses, with a median of two units of erythrocytes transfused. Severe leukopenia ( < 1,000 leukocytes/mm3) was rare (1.5% of all patients) and was not associated with any infectious complications. Severe thrombocytopenia ( < 30,000 platelets/mm3) occurred in 2.2% of all treatment cycles, with two patients experiencing a grade 3 hemorrhage, defined as gross blood loss, and one patient experiencing a grade 4 hemorrhage, defined as a debilitating blood loss. Defects in the coagulation pathway were common: abnormal partial thromboplastin time and prothrombin time values occurred in 64% and 25% of the treatment cycles, respectively. In addition, a mean clearance of 93% of lymphocytes from the peripheral blood was observed within 24 hours after initiating IL-2 therapy. This was followed by rebound lymphocytosis to a mean of 198% of baseline on posttreatment Day 4. There were no treatment-related deaths. During IL-2 therapy, adverse sequelae of anemia, thrombocytopenia, coagulopathy, and leukopenia were usually mild, transient and rarely limited therapy. A profound decrease in lymphocytes in the peripheral circulation occurred within 24 hours after initiating therapy, with a rebound occurring after stopping IL-2. No specific hematologic parameter was associated significantly with a patient's increased probability of responding to therapy.

Background: Oncolytic viruses (OVs) represent a promising option for treatment of advanced cancers. There are few studies assessing the effects of oncolytic viruses in renal cell carcinoma. Oncolytic measles virus (MV) is a novel viral platform that previously been shown to induce cell fusion and cytotoxicity in a CD46-dependent manner. The goals of our study are to identify a pharmacological agent that used in combination with oncolytic MV will enhance the virus cytotoxic effects in renal cell carcinoma (RCC) models. Results: To achieve this goal, we performed in vitro assays combining the Edmonston strain of Measles virus expressing eGFP (MV-GFP), whose oncolytic activity in vitro and in vivo has been demonstrated, with several targeted novel agents that include a new generation multikinase inhibitor used in the treatment of RCC, bromodomain inhibitors associated with epigenetic regulation and Triptolide (T) which has been reported as an apoptosis, ER stress, and oxidative stress inducer and inhibitor of angiogenesis. 786-0 (VHL-mut), A498 (VHL mutant), Caki-1 (VHL-wt) and ACHN (VHL-wt) RCC cells were seeded and treated with oncolytic MV, and the compounds including T. Cell viability as well as cytotoxicity were quantitated at 24, 48 and 72h. Evaluation of single agent activity showed that MV and T were associated with the most significant growth inhibitory or cytotoxic effects. Among the MV-drug combinations, we found that low dose of T was associated with the most significant augmentation of MV oncolysis in RCC cell lines, demonstrated by both viability cell count and by real time monitoring of cell growth by xCELLigence based assays. We found that the treatment sequence (virus infection followed by T treatment) was an important determinant of the combined tumor cytotoxic effects. In addition to enhanced tumor cytotoxicity, we also observed that T enhanced viral replication in RCC, which may explain in part the mechanisms of drug synergy. Finally, we investigated the molecular changes associated with RCC oncolysis by MV alone and in combination with T with RPPA (Reverse Phase Protein Array) and western blot validation and enhanced viral oncolysis induced by the MV-T combination was found to be associated with increased apoptosis (PARP cleavage), ER stress induction (pEIF2a, CHOP) and down regulation of survival and proliferation pathways (pAKT) 36h post-treatment. Conclusion: We identified a novel strategy to enhance RCC viral oncolysis by MV-T combination, by mechanisms that include enhanced viral replication with subsequent increase in the cell death, ER stress pathways and down regulation of pAKT. Current efforts are focused on identifying in vivo antitumor effects and mechanisms of this combination that will open new horizons for the development of rational combinations to improve oncolytic measles virotherapies in RCC, which could lead to long term responses/cures in this disease. Citation Format: Valery A. Chavez, Natasha Khatwani, Ashok Saluja, Jaime Merchan. A novel virus-drug combination to enhance oncolysis in renal cell carcinoma [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 4581.

Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses, which preferentially replicate in and kill cancer cells while sparing healthy cells, and induce anti-tumor immunity. OV-induced tumor immunity can be enhanced through viral expression of anti-tumor cytokines such as interleukin 12 (IL-12). IL-12 is a potent anti-cancer agent that promotes T-helper 1 (Th1) differentiation, facilitates T-cell-mediated killing of cancer cells, and inhibits tumor angiogenesis. Despite success in preclinical models, systemic IL-12 therapy is associated with significant toxicity in humans. Therefore, to utilize the therapeutic potential of IL-12 in OV-based cancer therapy, 25 different IL-12 expressing OVs (OV-IL12s) have been genetically engineered for local IL-12 production and tested preclinically in various cancer models. Among OV-IL12s, oncolytic herpes simplex virus encoding IL-12 (OHSV-IL12) is the furthest along in the clinic. IL-12 expression locally in the tumors avoids systemic toxicity while inducing an efficient anti-tumor immunity and synergizes with anti-angiogenic drugs or immunomodulators without compromising safety. Despite the rapidly rising interest, there are no current reviews on OV-IL12s that exploit their potential efficacy and safety to translate into human subjects. In this article, we will discuss safety, tumor-specificity, and anti-tumor immune/anti-angiogenic effects of OHSV-IL12 as mono- and combination-therapies. In addition to OHSV-IL12 viruses, we will also review other IL-12-expressing OVs and their application in cancer therapy.

Phase II trial of weekly intravenous gemcitabine administration with interferon and interleukin-2 immunotherapy for metastatic renal cell cancer.

Background: Oncolytic viruses have emerged as promising therapeutic agents to selectively target, infect and destroy cancer cells while synergizing with novel immunotherapies including Checkpoint inhibitors (CPI) and Chimeric Antigen Receptor (CAR) T- cells to increase anti-tumor efficacy. We developed two novel oncolytic non-enveloped RNA viruses, IVX037 and IVX055, using a proprietary receptor-focused bio-selection platform technology. IVX037 and IVX055 are small, single stranded RNA viruses, utilizing independent cell surface receptors to facilitate tumor targeting, cell entry and subsequent potent lytic replication. Intratumoral (i.t) IVX037 challenge of human microsatellite-stable colorectal cancer (MSS-CRC) xenografts increases expression of PD-L1 and mediates a widespread inflammation phenotype, suggested to allow increased migration of anti-tumor lymphocytes, elevation of cellular targets for immune checkpoint and cell-based anti-cancer therapies. Methods: In vitro monolayer cultures of human cancers were challenged with various input multiplicities of IVX037 or IVX055 with lytic infection assessed by a XTT viability assay. For mouse models, immunocompromised mice (SCID or nu/nu) were seeded with single flank human tumor cell administrations. Following development of palpable tumors, IVX037 was administered via i.v or i.t routes. Calliper measurements were employed to assess tumor burden. Checkerboard titrations of IVX037 and a mesothelin targeted CAR-T were utilized to assess anti-tumor activity in monolayer cultures of human gastric cancer cells. Results: IVX037 demonstrated potent oncolytic in vitro activity in human ovarian, gastric, and hepatocellular cancer (HCC) cell cultures. IVX055 induced rapid cell lysis in non-small cell lung, HCC and human bladder cancer in vitro cell preparations. Intratumoral and intravenous administration of IVX037 in human tumor xenograft models using immunocompromised mice were well tolerated and displayed potent anti-tumor activity against ovarian, gastric and HCC cancers. In reference, to cell-based therapies, preliminary in vitrocombination studies with mesothelin-targeted CAR T-cells and IVX037 suggest enhanced tumor cell killing compared to that of either agent alone in a human gastric cancer cell culture model. Conclusions: The promising preclinical anti-tumor activity of IVX037 and IVX055 against a wide range of human malignancies warrants further clinical evaluation in combination with novel immunotherapy strategies. To this end, IVX037 is currently being investigated in an ongoing Phase 1b combination trial with sintilimab (anti-PD-1) in patients with advanced MSS-CRC, gastroesophageal, and ovarian cancer (NCT05427487). Future plans for IVX055 include evaluation in combination with immune checkpoint therapy in patients with advanced non-small cell lung cancer (NSCLC) bearing metastatic liver disease. Citation Format: Darren Shafren, Christine Lee, Jera Peters, Szun Tay, Chloe Evans, Min Quah. Novel oncolytic RNA viruses, IVX037 and IVX055, demonstrate potent antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 859.

Phase Ib Trial of Oncolytic Herpes Virus G207 Shows Safety of Multiple Injections and Documents Viral Replication

Sequential Sorafenib and Sunitinib for Renal Cell Carcinoma

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.

Oncolytic Newcastle disease virus expressing a checkpoint inhibitor as a radioenhancing agent for murine melanoma.

This phase I study in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of s.c. treatment of human recombinant interleukin 21 (IL-21). Phase I dose-escalation trial with treatment of three to six patients at each dose level, escalating from 3 to 300 μg/kg. Treatment was administered s.c. on an outpatient basis 3 days per week for 8 or 16 weeks. Twenty-six patients entered the study. Recombinant IL-21 was generally well tolerated, and dose-limiting toxicities (DLT) were first seen at dose levels of 200 and 300 μg/kg. The following four DLTs were observed in three patients: increased transaminases, increased hyperbilirubinemia, hypersensitivity reaction, and lethargy. The MTD was declared to be 200 μg/kg, although five of seven patients at the 300 μg/kg dose level experienced no DLTs. A treatment-related effect on soluble CD25 was observed at all dose levels and increased with dose level. Furthermore, higher doses induced interferon-γ, perforin, and granzyme B mRNA expression in peripheral blood, and granzyme B protein expression in both CD8(+) T cells and natural killer cells, consistent with the activation of cytotoxic lymphocytes. Three patients, one patient with MM and two with RCC, obtained a partial response. Outpatient treatment with s.c. administered IL-21 was tolerated and had dose-dependent pharmacodynamics. rIL-21 showed antitumor activity in patients with MM and RCC.

Interleukin-2 (IL-2), used alone or in combination with adoptive cellular therapy, is one of the most promising biologic therapeutic agents for cancer treatment. The National Biotherapy Study Group conducted 15 trials of continuous-infusion IL-2 involving 788 patients with cancer, 638 of whom were evaluable for tumor response. The protocols included administration of IL-2 and lymphokine-activated killer (LAK) cells, IL-2 and cyclophosphamide, IL-2 and tumor-infiltrating lymphocytes, IL-2 and alpha-interferon (IFN), IL-2 and tumor necrosis factor, and IL-2 and LAK alternating with combination chemotherapy. Responses were detected in 33 of 188 patients (18%) with melanomas, 13 of 167 (8%) with renal cell carcinomas, and 1 of 76 (1%) with colorectal cancers. The median survival times in patients with melanoma and renal cell cancer were 9.6 and 9.3 months, respectively. The proportion of patients surviving 1 year were 35% and 43%, respectively. There were responses in 8 of 51 patients (16%) with lung cancer, but many of these patients received IL-2 and LAK alternating with platinum-based chemotherapy. Four of 23 patients (17%) responded who had breast cancer and received IL-2 and IFN. The protocols involving IL-2 plus adoptive cellular therapy produced a higher response rate than those not involving activated cells (48 of 312 [15%] versus 24 of 326 [7%], P = 0.003); however, there was no difference in survival. There was a 1.8% mortality rate attributed to the complications of IL-2 itself. IL-2 produces durable tumor responses in some patients, especially in those with melanoma and renal cell carcinoma. Because the drug's toxicity is significant and the overall response rates are low, patient selection may be the most important factor in the clinical use of continuous-infusion IL-2 therapy.