High-dose Interleukin-2 Therapy Research Articles

Is There a Current Role for Combination Chemotherapy or High-Dose Interleukin 2 in Melanoma?

Immune checkpoint inhibition and targeted therapies have revolutionized the treatment of melanoma. However, chemotherapy and interleukin 2 (IL-2) therapy may still have a role in the later-line treatment of patients who do not have durable responses to other treatments. Chemotherapy can work transiently in patients whose disease has progressed on immune checkpoint inhibitors and for whom there are no appropriate targeted therapy options. High-dose IL-2 therapy can still be effective for a very small number of patients following progression on other therapies. In addition, modified IL-2 agents and IL-2 in combination with tumor-infiltrating lymphocyte therapy may play a role in future treatments for melanoma.

IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein.

Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin-2 (IL-2), a cytokine critical to T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation, and antitumor immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Rα with higher affinity, triggers STAT5 activation, and drives CD8+ T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Last, we show that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.

Selective Agonism of Intermediate-Affinity IL-2 Receptor Promotes Systemic Antitumor Responses in Combination with Radiotherapy in Metastatic Lung Cancer

<h3>Purpose/Objective(s)</h3> For immune checkpoint inhibitor-resistant patients, adding interleukin-2 (IL-2) may aid antitumor responses by stimulating effector T cells and NK cells. Unfortunately, high-dose IL-2 therapy has limited clinical utility due to adverse events and stimulation of immunosuppressive regulatory T cells (T_regs). Nemvaleukin alfa (nemvaleukin) is a novel engineered cytokine that selectively binds to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8⁺ T and NK cells, with minimal expansion of T_regs. Thus, Nemvaleukin may be beneficial in combination with radiation therapy (RT) and immunotherapy. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462 (the murine ortholog of Nemvaleukin, a.k.a. mNemvaleukin), RT, and immunotherapy in multiple mouse tumor models. <h3>Materials/Methods</h3> In a bilateral 344SQ lung adenocarcinoma murine model, primary tumors were treated with high-dose RT (HDRT; 12 Gy per fraction for 3 fractions), and secondary tumors were observed for evidence of abscopal effects. In another model for low absolute lymphocyte count (ALC), we used 2 Gy total body irradiation (TBI) three days before HDRT and RDB 1462. In a third MC38-gp100 mouse model, tumors were irradiated with low-dose RT (LDRT; 3 fractions of 1 Gy each) followed by pmel-1 T cell infusion after 24 hours, and RDB 1462 administration 12 hours thereafter. We performed immune phenotyping by flow cytometry; analyzed 770 immune-related genes using a multiplex analysis platform; also performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit. <h3>Results</h3> In 344SQ-parental lung adenocarcinoma, we combined HDRT with escalating doses of RDB 1462 at various timepoints, resulting in significant tumor reduction in both irradiated and unirradiated (abscopal) tumors compared with HDRT or RDB 1462 therapy alone. HDRT+RDB 1462 increased the numbers and activity of tumor-specific CD8⁺ T cells, NK cells, and memory T cells without drastically increasing T_regs, as evidenced by peripheral and tumor-infiltrating immune phenotypic and functional analyses. T cells showed increased receptor clonality and diversity in groups receiving HDRT+RDB 1462. The addition of anti-PD-1 to HDRT+RDB 1462 further increased antitumor control of both irradiated and abscopal tumors, reduced lung metastases, and prolonged survival. The antitumor effects of HDRT and RDB 1462 persisted even in mice with low ALC. The addition of LDRT contributed to increased tumor-specific T cells that were expanded by RDB 1462 with increased infiltration of Thy1.1⁺ CD8⁺ T cells. <h3>Conclusion</h3> The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD-1 or adoptive T cell therapy.

Acute and Chronic Cardiopulmonary Effects of High Dose Interleukin-2 Therapy: An Observational Magnetic Resonance Imaging Study.

High dose interleukin-2 (IL-2) is known to be associated with cardiopulmonary toxicity. The goal of this study was to evaluate the effects of high dose IL-2 therapy on cardiopulmonary structure and function. Combined cardiopulmonary magnetic resonance imaging (MRI) was performed in 7 patients in the acute period following IL-2 therapy and repeated in 4 patients in the chronic period. Comparison was made to 10 healthy volunteers. IL-2 therapy was associated with myocardial and pulmonary capillary leak, tissue oedema and cardiomyocyte injury, which resulted in acute significant left ventricular (LV) dilatation, a reduction in LV ejection fraction (EF), an increase in LV mass and a prolongation of QT interval. The acute effects occurred irrespective of symptoms. In the chronic period many of the effects resolved, but LV hypertrophy ensued, driven by focal replacement and diffuse interstitial myocardial fibrosis and increased cardiomyocyte mass. In conclusion, IL-2 therapy is ubiquitously associated with acute cardiopulmonary inflammation, irrespective of symptoms, which leads to acute LV dilatation and dysfunction, increased LV mass and QT interval prolongation. Most of these effects are reversible but IL-2 therapy is associated with chronic LV hypertrophy, driven by interstitial myocardial fibrosis and increased cardiomyocyte mass. The findings have important implications for the monitoring and long term impact of newer immunotherapies. Future studies are needed to improve risk stratification and develop cardiopulmonary-protective strategies.

54-Year-Old Man With Acute Dyspnea on Exertion

54-Year-Old Man With Acute Dyspnea on Exertion

High-dose interleukin-2 therapy related adverse events and implications on imaging.

High-dose interleukin-2 (HDIL-2) therapy was initially approved by the U.S. Food and Drug Administration for metastatic renal cell carcinoma (mRCC) and metastatic melanoma. IL-2 is able to promote CD8+ T cell and natural killer (NK) cell cytotoxicity to increase tumoricidal activity of the innate immune system. HDIL-2 therapy is associated with a wide spectrum of immune-related adverse events (irAEs) that can be radiologically identified. HDIL-2 toxicity can manifest in multiple organ systems, most significantly leading to cardiovascular, abdominal, endocrine, and neurological adverse events. The collective impact of the irAEs and the rise of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors led to the demise of HDIL-2 as a primary therapy for mRCC and metastatic melanoma. However, with innovation in ICIs and the creation of mutant IL-2 conjugates, there has been a drive for combination therapy. Knowledge of the HDIL-2 therapy and HDIL-2 related adverse events with radiology relevance is critical in diagnostic image interpretation.

OrthoCARs: Engineered human IL-2/IL-2Rb orthogonal pairs selectively enhance CAR T cell antitumorefficacy

CAR T cell therapy has demonstrated remarkable clinical efficacy against relapsed and refractory hematological malignancies, such as B cell non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL) (Neelapu et al. NEJM, 2017; Schuster et al. NEJM, 2018; Turtle et al. Sci Trans Med, 2016). Despite these advances, prominent barriers including poor T cell effector function, lack of proliferation, and limited CAR T cell persistence prevent CAR T cell therapies from reaching their full curative potential (Srivastava and Riddell, Journal of Immunology, 2019). Interleukin-2 (IL-2) is a potent stimulator of CD4 and CD8 T cell proliferation, survival, and cytotoxic function, thereby making it an attractive molecule to support CAR T cell therapy. However, therapeutic use of IL-2 is limited by systemic toxicity due its promiscuous activation of undesired immune cell populations, including non-tumor reactive T cells and NK cells (Rosenberg et al. Journal of Immunology, 2014). To facilitate selective ex vivo and in vivo expansion of engineered T cells we have developed a human orthogonal (ortho) ligand/receptor system consisting of a pegylated, IL-2 mutein (STK- 009) that does not significantly activate the wild type receptor and a mutated IL-2 Receptor Beta (orthoIL-2Rβ) that does not significantly respond to its native ligand, wild type IL-2. This system enables in vivo IL-2 signaling in engineered cells that express the orthoIL-2Rβ while avoiding signaling in bystander T cells and NK cells. Here, we demonstrate the ability of the STK-009/orthoIL-2Rb ligand/receptor pair to selectively potentiate human orthoIL-2Rb (hoRb) expressing CD19 CAR T cells (CD19 orthoCAR T cells) in vitro and in vivo. We also demonstrate that STK-009 is selective for the orthogonal IL-2Rb and in a non-human primate model does not potentiate wild type T or NK cells and shows no evidence of toxicity. The STK-009/CD19 orthoCAR T platform was evaluated in a disseminated Raji mouse model of aggressive lymphoma. Subcutaneous administration of STK-009 dramatically expanded the CD19 orthoCAR T cells possessing a clinically favorable TSCM and TEMRA immunophenotype and significant antitumor efficacy was observed even at doses of CAR T cells typically regarded as sub-efficacious. When STK-009 dosing was stopped after complete tumor responses, CD19 orthoCAR T cells contracted as expected. Subsequent redosing of STK-009 in these tumor free mice re-expanded CD19 orthoCAR T cell levels demonstrating the on-demand control of the STK-009/orthoCAR T cell platform. Given the deep and durable responses we observed in the disseminated Raji model, we subsequently invested investigated the efficacy of the STK-009/orthoCAR T cell platform in a subcutaneous Raji model of lymphoma characteristically resistant to CAR T cell therapy. No significant anti-tumor effect was observed in mice treated with either CAR T cells alone or the combination of high dose wild-type IL-2 and CAR T cells. The subcutaneous administration of STK-009 in combination with a sub-efficacious dose of CD19 orthoCAR T cells demonstrated significant expansion of the CD19 orthoCAR T cells with the clinically favorable TSCM and TEMRA immunophenotype and potent anti-tumor efficacy in this subcutaneous lymphoma model, demonstrating the selective potentiation of the CD19 orthoCAR T cells in response to STK-009. The toxicity of STK-009 was evaluated in a non-human primate dose-escalation study. Subcutaneous administration STK-009 at anticipated therapeutic doses showed no evidence of toxicity or biological effect on immune cells expressing the wild-type IL-2 receptor. Pharmacokinetic analysis of STK-009 in this study showed stable exposure with minimal clearance, demonstrating the selectivity of STK-009. These findings validate an orthogonal platform that selectively drives potent T cell effector functions of engineered cells without the toxicities mediated by NK cells or non-tumor specific T cells associated with high dose IL-2 therapy. These results demonstrate the ability of this orthogonal platform to improve the efficacy and durability of CAR T cell therapies. Disclosures Aspuria: Synthekine: Current Employment. Bauer:Synthekine: Current Employment. vivona:Synthekine: Current Employment. de Waal Malefyt:Synthekine: Current Employment. Kastelein:Synthekine: Current Employment. Oft:Synthekine: Current Employment. Emmerich:Synthekine: Current Employment. Rokkam:Synthekine: Current Employment. Kauder:Synthekine: Current Employment. McCauley:Synthekine: Current Employment. Riener:Synthekine: Current Employment. Verma:Synthekine: Current Employment.

The Immunotherapy Landscape in Renal Cell Carcinoma.

The past 30years have borne witness to a gradual evolution in the treatment landscape of advanced renal cell carcinoma (aRCC). Early immunotherapy approaches such as interferon-α and high-dose interleukin-2 (IL-2) therapy in this immunogenic tumor provided durable responses in only a minority of patients and came with toxic side effects. A growing understanding of the tumor biology elucidated pathways of tumorigenesis, which in turn revealed novel targets amenable to targeted therapies. Inhibition of angiogenesis and cell signaling emerged as cornerstones of treatment with the approval of bevacizumab and several pan-kinase and tyrosine kinase inhibitors. Though effective, their use has been limited by low rates of durable response, resistance, and side effects. The immunotherapy revolution of the past decade has led to immunotherapy-based combination regimens such as ipilimumab plus nivolumab, pembrolizumab plus axitinib, and avelumab plus axitinib, displacing single agent anti-angiogenic therapy in the first-line setting by demonstrating durable responses and improved survival over sunitinib. These immunotherapy-based combinations define first-line standard of care for aRCC today. The pipeline of second-line agents for consideration in patients who have disease progression despite immunotherapy regimens is robust but still in early stages of development.

Abundant CD8+ tumor infiltrating lymphocytes and beta-2-microglobulin are associated with better outcome and response to interleukin-2 therapy in advanced stage clear cell renal cell carcinoma

Studies assessing tumor-infiltrating lymphocytes (TILs) in clear cell renal cell carcinoma (ccRCC) and clinical outcomes have mixed results. Given fundamental interaction of MHC class I with CD8+ T-cells, we hypothesized that expression of MHC class I associated protein, beta-2-microglobulin (B2M), may be an important immunologic marker in RCC. We sought to understand potential implications of CD8 + TILs and tumor B2M expression on overall survival and response to high-dose interleukin-2 (IL-2) therapy, in a cohort of patients with high-stage (clinical stage III and IV) ccRCC. Four tumor regions from 56 patients with ccRCC were retrospectively assessed immunohistochemically. At a median follow-up time of 33 months, 22 (39%) patients had died of disease, 23 (41%) were alive disease, and 11 (20%) had no evidence of disease. Tumors with high CD8 + TILs had a significantly lower death rate [hazard ratio (HR): 0.33, p = 0.02]. CD8 + TILs correlated with B2M expression (p = 0.007). On multivariable analyses, patients with both high B2M and CD8 + TILs had lower death rate (HR: 0.27, p = 0.03). Within the subgroup treated with IL-2 (n = 27, 48%), tumors with high CD8 + TILs were more likely to respond to IL-2 therapy [coefficient (coef): 1.6, p = 0.05]. On multivariable analyses, tumors with a combination of both high B2M expression and high CD8 + TILs also showed trend to responding to IL-2 therapy (coef: 2.5, p = 0.06). In conclusion, abundant CD8+ TILs and high tumor expression of beta-2-microglobulin were good prognostic indicators associated with longer survival in patients with high-stage ccRCC. Abundant CD8+ TILs may predict response to IL-2 therapy.

Rigor prophylaxis in stage IV melanoma and renal cell carcinoma patients treated with high dose IL-2

BackgroundRigors are a significant adverse event during interleukin-2 (IL2) therapy for metastatic melanoma and renal cell carcinoma. Meperidine has been a mainstay for rigor prophylaxis but there is a paucity of data regarding possible alternatives.MethodsNinety one patients receiving IL2 therapy for metastatic renal cell carcinoma and melanoma at Huntsman Cancer institute (HCI), Utah from May 2009 to October 2016 were retrospectively evaluated for rigor prophylaxis. Forty two patients received meperidine and 49 received tramadol. Rigors were tabulated using the proxy of number of doses of as needed (PRN) rigor medications and normalized by IL2 doses. Other outcomes of fever, hypotension, and renal insufficiency were noted on a binary scale and normalized by cycles. Statistical analysis was performed utilizing univariate and multivariate negative binomial models.ResultsNinety one patients were identified with metastatic melanoma or RCC who received high dose IL2 therapy. Forty two received meperidine and 49 received tramadol prophylaxis for rigors. Univariate negative binomial analysis shows incidence rate ratios (IRR): fever 0.41 (95% CI 0.28–0.62, p-value < 0.001), hypotension 1.7 (95% CI 1.11–2.61, p-value 0.015), renal insufficiency 0.58 (95% CI 0.35–0.98, p-value 0.041), rigors per all PRN meds 1.01 (95% CI 0.79–1.28, p-value 0.964), and rigors via opioid PRN meds 0.85 (95% CI 0.67–1.07, p-value 0.168). Multivariate negative binomial analysis shows IRR: fever 0.59 (95% CI 0.28–1.24, p-value 0.163), hypotension 0.93 (95% CI 0.43–2.03, p-value 0.864), renal insufficiency 1.1 (95% CI 0.52–2.32, p-value 0.807), rigors per al PRN meds 0.92 (95% CI 0.67–1.26, p-value 0.604), and rigors via opioid PRN 0.9 (95% CI 0.65–1.26, p-value 0.554).ConclusionUnivariate models indicated meperidine pre-treatment was associated with significantly lower rates of fever and renal insufficiency whereas tramadol was associated with significantly lower rate of hypotension. However, when controlled for demographics and other treatment differences, these differences were no longer significant.

Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma

Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment. High-dose interleukin-2 (HDIL-2) therapy remains a reasonable treatment option in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and have minimal comorbid conditions. In the near future, these agents are likely to be surpassed by cabozantinib and by combination immune checkpoint inhibitor therapy with nivolumab and ipilimumab. Independent review has recently confirmed superiority of first-line cabozantinib over sunitinib in a phase 2 trial of 157 patients with intermediate or poor risk mccRCC (progression-free survival [PFS] 8.6 vs 5.3months, hazard ratio [HR] 0.48, p = 0.0008). In a separate study of 1096 patients treated with either upfront sunitinib or the combination of nivolumab and ipilimumab, those with intermediate and poor risk had significant improvement in both PFS (11.6 vs 8.4months, HR 0.82, p = 0.0331) and OS (not reached vs 26months, p < 0.0001). Responses were greater in patients with positive programmed death receptor ligand-1 (PD-L1) tumor staining, and pending regulatory approval may become standard of care in untreated patients with intermediate to poor risk disease with positive PD-L1 status. This likely represents the beginning of additional novel immunotherapy combinations for the first-line treatment of mccRCC.

Improved survival and tumor control with Interleukin-2 is\xa0associated with the development of immune-related adverse events: data from the PROCLAIMSM registry

BackgroundImmune related adverse events (irAEs) are associated with immunotherapy for cancer and while results suggest improvement in tumor control and overall survival in those experiencing irAEs, the long-term impact is debated. We evaluated irAE reports related to high dose interleukin-2 therapy (IL-2) documented in the PROCLAIMSM registry data base from 2008 to 2016 (NCT01415167, August 9, 2011).MethodsReports on 1535 patients, including 623 with metastatic melanoma (mM) and 919 with metastatic renal cell cancer (mRCC) (7 patients had both diseases), were queried for irAEs. The timing of the event was categorized as occurring before, during or after IL-2 or related to any checkpoint inhibitor (CPI). mM patients and mRCC patients were analyzed separately. Tumor control [complete + partial response + stable disease (CR + PR + SD) was compared between those experiencing no irAE versus those with the development of irAEs. Survival was analyzed by tumor type related to timing of irAE and IL-2, and in those with or without exposure to CPI.ResultsMedian follow-up was 3.5+ years (range 1–8+ years), 152 irAEs were reported in 130 patients (8.4% of all PROCLAIMSM patients): 99 (16%) in mM and 53 (5.8%) in mRCC patients. 31 irAEs occurred prior to IL-2, 24 during IL-2, and 97 after IL-2 therapy. 74 irAEs were attributed to IL-2 only (during/ after IL-2). Of the 97 post IL-2 irAEs, 24 were attributed to CPI, and 15 could not be distinguished as caused by IL-2 or CPI. Tumor control was 71% for those experiencing irAE, and 56% for those with no irAE (p = 0.0008). Overall survival was significantly greater for those experiencing irAEs during/ after IL-2 therapy, compared to those with no irAE or irAE before IL-2 therapy, in mM patients, median 48 months vs 18 months (p < 0.0001), and in mRCC patients, median 60 months vs 40 months (p = 0.0302), independent of CPI-related irAEs. IL-2-related irAEs were primarily vitiligo and thyroid dysfunction (70% of IL-2 related irAEs), with limited further impact.ConclusionsirAEs following IL-2 therapy are associated with improved tumor control and overall survival. IrAEs resulting from IL-2 and from CPIs are qualitatively different, and likely reflect different mechanisms of action of immune activation and response.

Abstract 3675: Novel immune oncology strategy for targeted cytotoxic lymphocyte activation

Abstract High-dose interleukin 2 (IL2) therapy was the first FDA-approved immunotherapy, and still has an exceptionally high true long-term cure rate for metastatic cancer. However, IL2 therapy has fallen out of favor due to systemic toxicity and off-target side effects. We have recently described a novel fusion cytokine comprised of a mutant form of IL2 with inhibited α-receptor binding and an NKG2D-binding viral decoy protein called Orthopox Major Histocompatibility Complex Class I-like Protein (OMCP). Unlike wild-type IL2, our fusion cytokine (OMCP-mutIL2) binds to and activates only NKG2D expressing cytotoxic lymphocytes. This targeted IL2 activity results in superior efficacy and decreased toxicity over wild-type IL2 therapy. Here, we present data which further establishes the superior efficacy of OMCP-mutIL2 therapy as measured by biomarkers such as systemic cytokine production and tumor lymphocyte infiltration. Additionally, we present data which evaluates OMCP-mutIL2 therapy as a potentiator of PD1 checkpoint inhibitor therapy. To evaluate tumor lymphocyte infiltration mice with established Lewis Lung Carcinoma (LLC) flank tumors were treated for three days with either saline, wild type IL2, or OMCP-mutIL2 and tumor infiltrating lymphocytes evaluated flow cytometrically. A trend for increased tumor infiltrating NK cells was evident for both IL2 and OMCP-mutIL2 treated groups over saline controls, and OMCP-mutIL2 tended to increase tumor infiltrating CD8+ T cells over either IL2 or saline controls was evident as well. Additionally, tumor infiltrating CD8+ T cells in IL2-treated mice had a higher level of exhaustion over OMCP-mutIL2 treated mice as measured by PD-1 expression. Tumor infiltrating CD4+ T cells also showed a trend toward a Foxp3 regulatory phenotype in IL2 treated mice over OMCP-mutIL2. To study cytokine serum profile mice were treated with high dose OMCP-mutIL2 with or without NK depletion and serum cytokine levels measured by cytometric bead array. Serum cytokine analysis of mice treated with supra-therapeutic doses of OMCP-mutIL2 did not reveal an increase in pro-inflammatory cytokines TNF-α, IFN-γ, and IL-6. A significant increase in serum levels of G-CSF was evident in NK cell sufficient mice treated with OMCP-mutIL2. Combination immunotherapy was initiated by the addition of PD-1 blockade (clone RMPI-14) to OMCP-mutIL2 therapy in a lung LLC tumor model. Combination therapy led to near complete control of LLC growth in the lung compared to OMCP-mutIL2 or PD-1 blockade alone. The data presented here suggest that in addition to our previously published data suggesting increased safety of OMCP-mutIL2 over high-dose IL2 therapy, OMCP-mutIL2 therapy may be functionally superior to classic high-dose IL2 therapy. Continued development of OMCP-mutIL2 is ongoing. Citation Format: Eric Lazier, Sarah Hein, John Westwick, Dan Watkins, Alexander S. Krupnick. Novel immune oncology strategy for targeted cytotoxic lymphocyte activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3675. doi:10.1158/1538-7445.AM2017-3675

The Role of High Dose Interleukin-2 in the Era of Targeted Therapy

We assessed survival outcomes following high dose interleukin-2 in a contemporary cohort of patients during the era of targeted agents. We retrospectively reviewed the records of patients with metastatic renal cell carcinoma treated with high dose interleukin-2 between July 2007 and September 2014. Clinicopathological data were abstracted and patient response to therapy was based on RECIST (Response Evaluation Criteria In Solid Tumors), version 1.1 criteria. The Kaplan-Meier method was used to estimate progression-free and overall survival in the entire cohort, the response to high dose interleukin-2 in regard to previous targeted agent therapy and the response to the targeted agent in relation to the response to high dose interleukin-2. We identified 92 patients, of whom 87 had documentation of a response to high dose interleukin-2. Median overall survival was 34.4 months from the initiation of high dose interleukin-2 therapy in the entire cohort. Patients who received targeted therapy before high dose interleukin-2 had overall survival (median 34.4 and 30.0 months, p = 0.88) and progression-free survival (median 1.5 and 1.7 months, p = 0.8) similar to those in patients who received no prior therapy, respectively. Additionally, patients with a complete or partial response to high dose interleukin-2 had similar outcomes for subsequent targeted agents compared to patients whose best response was stable or progressive disease (median overall survival 30.1 vs 25.4 months, p = 0.4). Our data demonstrate that patient responses to high dose interleukin-2 and to targeted agents before and after receiving high dose interleukin-2 are independent. As such, carefully selected patients should be offered high dose interleukin-2 for the possibility of a complete and durable response without the fear of limiting the treatment benefit of targeted agents.

Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma.

High-dose interleukin-2 (HD IL-2) was approved for treatment of metastatic renal cell carcinoma (mRCC) in 1992 and for metastatic melanoma (mM) in 1998, in an era predating targeted therapies and immune checkpoint inhibitors. The PROCLAIMSM registry was established to collect and analyze data for patients treated with HD IL-2 in the current era. This analysis includes 170 patients with mM and 192 patients with mRCC treated between 2005 and 2012 with survival data current as of July 27, 2015. For patients with mM, complete response (CR) was observed in 5 %, partial response (PR) in 10 %, stable disease (SD) in 22 %, and 63 % had progressive disease (PD). The median overall survival (mOS) for these patients was 19.6 months, with a median follow-up of 43.1 months. The mOS was not reached for patients achieving CR or PR, and was 33.4 months for patients with SD. For patients with mRCC, 6 % achieved CR, 9 % had PR, 22 % had SD, and 62 % had PD. The mOS was 41 months, with a median follow-up of 46.6 months. The mOS for patients who had CR and PR was not reached and was 49.6 months for patients with SD. There were no treatment-related deaths among 362 patients. The duration of mOS for patients with mM and mRCC is longer than historically reported. These data support a continued role for IL-2 in the treatment of eligible patients with mM or mRCC and warrant further evaluation of HD IL-2 in combination or sequence with other therapeutic agents.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-016-1910-x) contains supplementary material, which is available to authorized users.

Phase 2 Trial of High-Dose Interleukin-2 (IL-2) and Stereotactic Ablative Radiation Therapy (SABR) for Metastatic Clear Cell Renal Cell Carcinoma (mRCC)—Interim Analysis of i-SAbR IL-2 Trial

Phase 2 Trial of High-Dose Interleukin-2 (IL-2) and Stereotactic Ablative Radiation Therapy (SABR) for Metastatic Clear Cell Renal Cell Carcinoma (mRCC)—Interim Analysis of i-SAbR IL-2 Trial

Conditional survival of metastatic renal cell carcinoma patients treated with high-dose interleukin-2.

Conditional survival (CS) is a clinically useful prediction measure which adjusts a patient’s prognosis based on their duration of survival since initiation of therapy. CS has been described in numerous malignancies, and recently described in patients with metastatic renal cell carcinoma (mRCC) who received vascular endothelial growth factor tyrosine kinase inhibitor (VEGFTKI) therapy. However, CS has been not reported in the context of mRCC treated with high-dose interleukin-2 therapy (HDIL-2). A total of 176 patients with histologically confirmed metastatic clear cell RCC (mccRCC) treated with HDIL-2 at the University of Utah Huntsman Cancer Institute from 1988–2012 were evaluated. Using the Heng/IMDC model, they were stratified by performance status and prognostic risk groups. Two-year CS was defined as the probability of surviving an additional two years from initiation of HDIL-2 to 18 months after the start of HDIL-2 at three-month intervals. The median overall survival (OS) was 19.9 months. Stratifying patients into favourable (n = 35; 20%), intermediate (n = 110; 63%), and poor (n = 31; 18%) prognostic groups resulted in median OS of 47.5 (HR 0.57, 95% CI 0.35–0.88, p = 0.0106 versus intermediate), 19.6 (HR 0.33, 95% CI 0.10–0.33, p < 0.0001 versus poor), and 8.8 (HR 5.34, 95% CI 3.00–9.62, p < 0.0001 versus favourable) months respectively. Two-year overall CS increased from 43% at therapy initiation to 100% at 18 months. These results have significant ramifications in prognostication. Furthermore, it is important when counseling patients with mccRCC who have completed treatment with HDIL-2 and are in active follow-up.

Current Immunotherapies for Renal Cell Carcinoma.

Immunotherapy, though not a new modality for cancer treatment, has enjoyed renewed vigor and interest over the last several years. Multiple new targets have been identified, and therapeutic agents are in varying stages of development, with some agents having obtained regulatory approval for administration in the clinic. Renal cell carcinoma is known to potentially respond favorably to immunotherapy, with a small subset of patients achieving durable responses to high dose interleukin-2 therapy. Consequently, renal cell carcinoma is one of the many tumor types in which the efficacy of new agents is being investigated. Here we examine the landscape of current immunotherapeutic options for renal cell carcinoma, including cytokine therapy, immune checkpoint blockade, hematopoietic stem cell transplant, and vaccine therapy. We review approved immune directed therapies as well as new agents undergoing clinical trials in renal cell carcinoma. Immunotherapy has been and remains a promising treatment modality in this tumor type. Hopefully the approval of newer agents will translate into more accessible and efficacious options for patients and oncologists.

Near complete remission of pulmonary metastases in triple negative breast cancer (TNBC) using low-dose immune checkpoint (IC) inhibitors with high dose (HD) interleukin-2 (IL-2) and fever range hyperthermia.

e23111 Background: TNBC is more aggressive, has shorter disease-free and overall survival times than other breast cancer subtypes. Due to the lack of personalized therapies interest is increasing for novel strategies in the metastatic setting. Scientific basis:prolonged low dose anti-CTLA-4 and anti-PD-1 IC blockade with HD IL-2 treatment would be safe and effective in patients with high tumor burden. Methods: Diagnosis of a 50-yr old female patient was primary TNBC with lymphadenopathy and disseminated lung metastases. First, an off-label low-dose PD-1 IC inhibitor nivolumab (0.5 mg/kg) with CTLA-4 IC inhibitor ipilimumab (0.3 mg/kg) was administered weekly, over three weeks. This was accompanied by loco-regional hyperthermia with radiofrequency fields (13.56 MHz) 3 times per week (max. output 400 W) over the thoracic region in combination with Vitamin-C (0.5 g/kg) and alpha lipoic acid (600 mg) over three weeks. This was followed by long duration fever range whole body hyperthermia in combination with low dose cyclophosphamide (300 mg/m²) to down modulate Treg cells. Then, a HD IL-2 (54 Mio/m2 as decrescendo regimen) therapy was administered under Taurolidine protection for five days. Results: The patient presented with widespread disease with a Karnofsky score (Ks) of 80%, felt severe pain in the left lateral chest wall during inspiration that became extremely painful during sneezing. She complained about severe shortness of breath (SOB) on exertion, lack of appetite, insomnia, and exhaustion. Six months later, chest X-ray demonstrated near complete remission of pulmonary metastases. SOB on exertion or any other cancer related symptoms vanished, Ks returned to 100%. Conclusions: We assumed that a frequently administered low dose IC blockade would prevent T cell exhaustion and premature apoptosis making main stream HD IL-2 stimulation treatment safer and more effective. Following the success of this woman, we treated seven more patients with disseminated metastases of different origins, who are responding similarly to the presented TNBC case. This combination treatment warrants further studies.

Phase II trial of high-dose interleukin-2 (IL-2) and stereotactic radiation therapy (SABR) for metastatic clear cell renal cell carcinoma (ccRCC): Interim analysis.

532 Background: We report a planned interim analysis of a single-arm, open-label, phase II trial of HD IL-2 and SABR in multiple ccRCC metastatic sites. Methods: Metastatic ccRCC patients eligible for IL-2 were enrolled and received SABR of 1 or 3 fractions (fx) to up to 6 sites. IL-2 (Proleukin) was administered within 84 hours from the last SABR fx at 600,000 IU/kg every 8h for up to 14 doses in a monitored setting followed by another week after a week break. Eligible (responding) patients received a second course in &gt; 12 weeks. The primary endpoint is the response rate (RR) as evaluated by iRECIST. The study is powered to detect a 60% improvement compared to the historically reported 23% RR for IL-2. Results: 16 patients were enrolled between August 2013 and July 2015; two were withdrawn from the study due to cardiac events prior to receiving IL-2 infusions. The median follow up was 9 months. A median of 2 (1-3) sites were treated with SABR with a median dose of 24.5 Gy (21-27 Gy) for single fx and 30Gy for 3 fx (25-33 Gy). All patients received the first week of IL-2 with a median of 10.5/14 doses; 64% received the second week (9/14) with a median of 7/14 doses. Two patients refused a second week of IL-2 and one was unable to receive it due to thyrotoxicosis. PICC line DVT delayed the second week of IL-2 in two patients. 29% of patients (4/14) received a second course of IL-2. The rate of grade 3 toxicity was 64% with no &gt; grade 3 toxicity. The overall toxicities were expected of IL-2 treatment, transient and resolved after treatment discontinuation. In two cases, grade 1 toxicity was attributed to SABR. At this interim, ten patients underwent at least two follow up scans and were evaluable for outcome analysis. The RR was 40%, with one patient presenting complete response and 3 patients showing partial response. The median duration of overall response was 5 months, with a median stable disease duration of 6 months. Local control rate for SABR-treated lesions was 95%. Conclusions: The addition of SABR to IL-2 increased the RR in mRCC patients of about 2-folds compared to IL-2 alone, despite the reduced number of patients receiving the second week of IL-2. No significant increase in toxicity was observed. Clinical trial information: NCT01896271.