HD IL-2 Research Articles

High-dose interleukin-2 (HD IL-2) for advanced melanoma: a single center experience from the University of Pittsburgh Cancer Institute

BackgroundDurable remissions are observed in a fraction of metastatic melanoma patients treated with high-dose interleukin-2 (HD IL-2). Early studies reported overall (OR) and complete response (CR) rates of 16% and 8% respectively. Toxicity limited use to specialized centers with standardized protocols. We report on 243 patients treated at the University of Pittsburgh in a non-intensive care unit (ICU) oncology specialty setting.MethodsClinical and radiological data were collected on 243 patients treated between 1992 and 2015. Each HD IL-2 cycle was given over 5 days, cycles were repeated after 9 days and courses (2 cycles) were repeated every 6–9 weeks in patients with stable or responding disease, for up to 3 courses total. Influence of baseline characteristics on outcomes was assessed using Kaplan-Meier estimates and Cox proportional hazards analysis.ResultsTwo hundred forty-three patients received 692 cycles (5270 doses) between 1992 and 2015. Two hundred thirty-seven patients were evaluable for response: OR rate 18.1% with CR rate 8.0%. Median overall survival (OS) 9.6 months in the entire cohort but 64.9 months in responders. Median number of cycles delivered was 2,and median number of doses per cycle was 8. Toxicity was consistent with prior reports. HD IL-2 required ICU transfers in 11 patients and 1 death was attributed to HD IL-2. Pre-treatment lactate dehydrogenase (LDH) levels correlated significantly with progression-free survival [1-2× upper limit normal (ULN) HR 1.95; >2× ULN HR 2.32] and overall survival (1-2× ULN HR 1.67; >2× ULN 2.49). Response to HD IL-2 and site of metastatic disease also correlated significantly with progression-free and overall survival.ConclusionsIn this large series of patients spanning more than two decades, OR/CR rates with HD IL-2 were 18.1%/8.0% respectively. Toxicity data was consistent with prior reports. Pre-treatment LDH values and site(s) of metastatic disease may be useful markers to select patients at greater likelihood of benefit to HD IL-2 therapy.

Long-term (LT) disease-free survival (DFS) of melanoma (MM) and renal cell cancer (RCC) patients following high-dose interleukin-2 (HD IL2).

e21005 Background: HD IL2 treatment (Tx) produces durable complete responses (CRs) and surgical CRs. Patients (pts) achieving partial response (PR) and stable disease (SD) demonstrate improved survival compared with pts who progress. Methods: 7 HD IL2 Tx centers identified pts with survival > 5 years (yrs) after HD IL2. DFS was from end of IL2 to January 2017. Tx courses generally consisted of 2 1-week cycles of HD IL2, 600,000-720,000 U/kg IV every 8 hours. We collected data on pts Tx with HD IL2 alone, or HD IL2 plus local Tx (surgery or radiation (SRS) leading to CR) with survival > 5 yrs after HD IL2 Tx. Results: 72 pts are reported: 29 RCC (male 22, female 7) and 43 mm (male 26, female 17). Median age at Tx of RCC is 54 yrs (range, 47-67 yrs) and of mm is 50 yrs (range, 24-72 yrs). Sites of metastatic disease for 26 mm pts were lymph nodes (LN) -18, lungs-12, bone-6, liver-9, brain-3, other organs-10 and for 22 RCC pts were lung-17, LN-5, adrenal-4, bone-3, other organs-8. Number of IL2 courses received: 1-10 pts, 1.5-4 pts, 2-28 pts, 2.5-5 pts, 3-24 pts, 4-one pt. Among the 29 RCC pts, there are 24 CRs, 3 surgical CRs and 2 PRs with no further Tx. Among 43 mm pts, there are 34 CRs, 2 near CRs, and 7 Surgical/SRS CRs. DFS in these pts after HD IL2 Tx ranges from 5+ yrs to 30+ yrs, median 10.5+ yrs. 10 RCC and 16 mm are alive > 5 - < 10 yrs after IL2, and 19 RCC and 27 mm are alive > 10 yrs after IL2. LT toxicity among these 72 pts includes hypothyroidism-5 pts, arthralgias/arthritis-5 pts, vitiligo-3 pts, and 1 pt each: neuropathy, PVCs, and normal pressure hydrocephalus. Additional pts may be added as records become available. Conclusions: We document LT DFS ( > 5 yrs) after CR or PR from HD IL2 alone. Surgical or SRS conversion of PR to CR can produce durable CRs. LT DFS was observed in pts with visceral and bone metastases, not only those with LN or lung sites. Neither age, sex, nor number of courses of IL2 predicted LT DFS. Chronic toxicity due to IL2 is uncommon in LT survivors.

The association of tumor infiltrating CD8+ and Foxp3+ cells with overall response rate (ORR) in metastatic renal cell carcinoma (mRCC) patients treated with high-dose aldesleukin (HD IL-2).

4576 Background: In the prospective, biomarker validation HD IL-2 “Select” study, durable remissions and prolonged survival were seen in both proposed “good” and “poor-risk” patients, based on clear-cell histology subclassification and carbonic anhydrase-9 (CA-9) IHC staining. Given the toxicity and limited efficacy of HD IL-2, efforts to improve its therapeutic index are warranted. Since the high-affinity receptor of IL2 is expressed on both T regulatory cells and activated effector T lymphocytes, we explored the association between HD IL-2 response and tumor infiltration of CD8+ T and FoxP3+cells. Methods: Archival tumor tissue was collected for pathologic analysis on 120 mRCC patients enrolled in the HD IL-2 “Select” trial.Density of tumor infiltrating CD8+ T cells and Foxp3+ cells (cell/mm2) were evaluated in the invasive margin (IM) and the tumor center (TC) by IHC and automated image analysis using Aperio algorithms. The association between ORR and immune cell density was assessed using Fisher exact test. Results: Tumor specimens of 89 patients were available for analysis. 24 pts experienced response (R, including 2 CR and 22 PR) and 65 pts did not respond (NR, including 11 SD and 54 PD). Baseline patient characteristics were similar between R and NR groups. A very high density of CD8+ cells in the IM, or a high density of Foxp3+ cells in the TC were significantly associated with ORR. A stronger association with ORR was found for patients having both high density of CD8+ cells in the IM and Foxp3+ cells in the TC. Conclusions: In this prospective, biomarker validation study, response to HD IL-2 was associated with a high density of CD8+ cells in the invasive margin, and a high density of Foxp3+cells in the tumor center. Independent validation is ongoing. To improve the predictive value of Foxp3, characterization of Foxp3 expressing cells (Tregs vs activated effector T cells) in highly infiltrated tumors is underway. [Table: see text]

Abstract B011: Human IL-2 mutant exhibits a higher antitumor efficacy and lower toxicity than wildtype IL-2 in different preclinical contexts

Abstract High dose IL-2 is registered for the treatment of melanoma and renal cell carcinoma, however this therapy has limited efficacy and severe toxicity. It has been shown that in patients HD IL-2 drives preferential expansion of regulatory T cells, which dampen the antitumor immunity. This results explain at least partially the limited efficacy of this therapy. In this work, we characterize a human IL-2 mutant which differs from wildtype IL-2 by four mutations at the interface with the a-subunit of IL-2R. In vitro, IL-2 mutant induces proliferation of CD8+CD44hi and NK1.1 cells as efficiently as wtIL-2 does, but it shows a reduced capacity to induce proliferation of CD4+Foxp3+ regulatory T cells. In vivo, IL-2 mutant clearly induces preferential proliferation of CD8+CD44hi witha quite reduced proliferation of CD4+Foxp3+ regulatory T cells. The IL-2 mutant shows higher antimetastatic effect than wtIL-2 in several transplantable tumor models. i.e. the experimental metastasis model of MB16F0; the experimental and spontaneous metastasis models for the mouse pulmonary carcinoma 3LL-D1222 and the metastasis mammary carcinoma 4T1. Moreover initial data also support a higher potency of this IL2 mutant, when used in combination with other immune-therapies. Relevantly, the IL-2 mutant also exhibits lower lung and liver toxicity than does wtIL-2 when used at high doses in mice. The IL-2 mutant described could be a good candidate for improving cancer therapy based on IL-2. Citation Format: Tania Carmenate, Magela Montalvo, Gertrudis Rojas, Dasha Fuentes, Kalet Leon. Human IL-2 mutant exhibits a higher antitumor efficacy and lower toxicity than wildtype IL-2 in different preclinical contexts [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B011.

Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIMSM

BackgroundThis analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2). Patients and MethodsPatients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in ProleukinR Observational Study to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIMSM) beginning in 2011. Statistical analyses were performed using datasets as of September 24, 2015. ResultsOverall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2. ConclusionsHD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients.

High-dose interleukin2 – a 10-year single-site experience in the treatment of metastatic renal cell carcinoma: careful selection of patients gives an excellent outcome

BackgroundVEGF-targeted therapy has become the mainstay of treatment for majority of mRCC patients. For most patients, benefit is short-lived and therefore treatment remains palliative in intent. HD IL2 is an...

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.

A retrospective analysis of High-Dose Interleukin-2 (HD IL-2) following Ipilimumab in metastatic melanoma

BackgroundHigh dose interleukin-2 (HD IL-2) can induce durable responses in a subset of patients leading to long-term survival. Immune checkpoint blockade (ICB) has demonstrated similarly durable responses in a larger...

Update on the overall survival of patients with metastatic melanoma treated with immune checkpoint blockade following initial treatment with HD IL-2.

e21039Background: High-dose interleukin-2 (HD IL-2) and immune checkpoint inhibitors can provide survival benefit in patients with metastatic melanoma (mM). The clinical impact of using these thera...

High dose Interleukin 2 (HD IL2) as 1st line treatment in metastatic renal cell carcinoma (mRCC): A 10-year single centre experience.

4555Background: Targeted therapy has become the treatment of choice for majority of mRCC cases in recently. For most, treatment benefit is short-lived and given with palliative intent. HD IL2 is an...

A Prospective Analysis of High-Dose Interleukin-2 (HD IL-2) following PD-1 inhibitor therapy in patients with metastatic melanoma and renal cell carcinoma.

e21006Background: PD-1/PD-L1 inhibitors (aPD-1) have demonstrated efficacy in the treatment of metastatic melanoma (MM) and advanced renal cell carcinoma (RCC). HD IL-2 can produce durable response...

Extension of overall survival in patients with metastatic renal cell carcinoma who received HD IL-2 followed by targeted therapy and/or immune checkpoint blockade from the PROCLAIM registry.

4548Background: High dose IL-2 (HD IL-2) can provide durable responses in patients with metastatic renal cell carcinoma (mRCC). PROCLAIM (www.proclaimregistry.com, NCT01415167) is an IL-2 registry ...

Efficacy and tolerability of high dose interleukin-2 (HD IL-2) after disease progression on targeted therapy (TT) for metastatic renal cell carcinoma (mRCC).

e16064Background: Approved first-line treatment for mRCC includes HD-IL2 and TT. TT is more commonly used given higher response rates, more favorable side effect profile, and oral administration. H...

Annual Hospital Volume of High Dose Interleukin-2 and Inpatient Mortality in Melanoma and Renal Cell Carcinoma Patients.

BackgroundImmunotherapy using high dose interleukin-2 (HD IL2) in patients with renal cell carcinoma (RCC) and melanoma is associated with severe toxicities. The association between annual hospital volume of HD IL2 and inpatient mortality is not well studied. In this study we aim to quantify the impact of annual hospital volume of HD IL2 on inpatient mortality using National Inpatient Sample (NIS) data.MethodsWe did a cross-sectional study using NIS, one of the largest inpatient datasets in United States, from 2003 to 2011. Patients with melanoma and RCC receiving HD IL2 were identified by ICD9 procedure code 00.15. The primary outcome was inpatient mortality. Using Joinpoint regression, which detects change in trend of inpatient mortality with change in annual volume, the hospitals were classified in three volume categories (low: 1–40, medium: 41–120, high: >120). Multivariate logistic regression was used to identify predictors of inpatient mortality controlling for confounders.ResultsFrom 2003 to 2011, 29,532 patients with RCC or melanoma who received HD IL2 were identified, and 124 died during the hospitalization (0.4%). The hospitals with low, medium and high annual volume had significant difference in inpatient mortality (0.83%, 0.29% and 0.13% respectively, p = 0.0003). On multivariate analysis, low volume hospitals were associated with significantly higher odds of inpatient mortality (OR 6.1, 95% CI 1.6–23.2, p = 0.003) as compared to high volume hospitals. Additionally, the hospitals with annual volume of 1–20 had even higher rates (1.31% vs. 0.13%, p<0.0001) and multivariate odds (OR 8.9, 95% CI 2.4–33.2, p = 0.0006) of inpatient mortality as compared to high volume hospitals.ConclusionsLower annual hospital volume of HD IL2 is associated with worse outcomes. Annual hospital volume of 1–40 and 1–20 treatments per year is associated with 6 and 9 times higher odds of inpatient mortality respectively as compared to high volume hospitals. Our findings provide preliminary evidence for a volume-outcome relationship for RCC and melanoma patients undergoing HD IL2 treatment. They support future volume-outcome analyses in relation to other anti-cancer therapies that require special training and expertise.

Durability of responses in patients with metastatic renal cell carcinoma treated with high-dose interleukin-2 (HD IL-2).

511 Background: HD IL-2 is FDA approved for advanced renal cell carcinoma (mRCC), however, the data supporting its use is 23 years old. In 2011, a HD IL-2 patient database was established called PROCLAIMSM, and comprises the largest active prospective collection of data from mRCC and metastatic melanoma (MM) patients receiving HD IL-2 treatment and provides longitudinal real-time insights into the clinical impact of sequencing drug treatments. These data report on the outcomes and interactions with prior targeted therapies in mRCC patients in the current era. Methods: Inclusion criteria require patients to receive at least one dose of HD IL-2. Patients who received HD IL-2 and had already undergone a post-treatment scan were not eligible. Survival analysis was performed by the method of Kaplan and Meier using datasets as of July 27, 2015. Results: The overall response rate (ORR) and median overall survival (mOS) are described in Table 1. The mOS was not reached (NR) for 364 patients. The 1, 2 and 3 year survival rates were 79%, 63%, and 51%, respectively. For patients with stable disease (SD), the mOS was not reached and the 1, 2 and 3 year survival rates were 96%, 80%, and 60% respectively. There was a significant difference in mOS between SD and progressive disease (PD) patients, NR vs 15.5 months, P&lt;.0001. The mOS was not reached for patients regardless of whether or not they received targeted therapy (TT) prior to HD IL-2. There were 4 reported treatment-related deaths in 364 patients (1.1%), none of these patients had prior TT. Conclusions: PROCLAIM data demonstrate that SD, previously grouped with the non-responders, is associated with extended survival rates. HD IL-2 is an active 2ndline treatment option for patients who have failed TT. These data support that HD IL-2 has a favorable safety profile and remains an effective therapy for eligible patients with mRCC. Clinical trial information: NCT01415167. [Table: see text]

Abstract B140: Overall survival of metastatic melanoma patients treated with HD IL-2 followed by immune checkpoint blockade of the CTLA-4 or the PD-1 pathways: Analysis of data on the current use of HD IL-2

Abstract Background: The PROCLAIMSM registry (www.proclaimregistry.com), created in 2011, is the largest collection of IL-2 treated patients in the US and provides real-time insights into sequencing or combining IL-2 with new and old therapies and how this may affect patient outcomes. Previously, we reported a median overall survival (mOS) of 20 months with a median follow-up of 37 months in metastatic melanoma (mM) patients treated with high dose IL-2 (HD IL-2) between 2007 and 2012 from a retrospective cohort. These findings led to the hypothesis that improved mOS may have been a result of subsequent salvage therapies, including checkpoint inhibitors. Purpose: To report on the analysis of survival data from 26 sites. Methods: Patients must have received at least one dose of HD IL-2 for this analysis. Those that received checkpoint therapy prior to HD IL-2 were excluded. Statistics and survival analysis on prospectively entered patients were performed on datasets as of March 16th, 2015. Results: The median overall survival (mOS) for the 236 patients was 18.4 months with a median follow-up of 21.7 months. Patients were stratified into three groups; HD IL-2 only (n=123), HD IL-2 followed by ipilimumab (Post ipi, n=78), and HD IL-2 followed by PD-1 inhibitors (Post αPD-1, n=35). There were four patients in the Post αPD-1 group that received anti-PD-L1 treatment. Patients in the HD IL-2 only, Post ipi, and Post αPD-1 groups achieved a mOS of 14, 15.7, and 28.7 months, respectively. The estimated 12-month survival rates were 56%, 64%, and 97%, respectively. There were 10/78 (13%) and 3/35 (8.6%) post therapy treatment-related incidences of autoimmune events in the Post Ipi and Post αPD-1 groups, respectively. No treatment related deaths were reported. Conclusions: This is the first report of clinical data relating to HD IL-2 use followed by checkpoint blockade of the PD-1 pathway. Treatment with anti-PD-1 after initial therapy with HD IL-2 had significantly prolonged survival compared to patients treated with ipilimumab. Moreover, improved survival was not observed in patients treated with follow-on ipilimumab compared to patients treated only with HD IL-2. Anti-PD-1 therapy after HD IL-2, appears to be safe, is therapeutically active. These data support the concept of investigating IL-2 therapy in combination or sequence with newly developed immune checkpoint inhibitors. Citation Format: Michael K.K. Wong, Michael A. Morse, David F. McDermott, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Sandra Aung. Overall survival of metastatic melanoma patients treated with HD IL-2 followed by immune checkpoint blockade of the CTLA-4 or the PD-1 pathways: Analysis of data on the current use of HD IL-2. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B140.

Cancer Immunotherapy with Interleukin-2—The PROCLAIMSM Registry

High dose interleukin (HD IL-2) is an approved therapy for the treatment of metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) that is capable of inducing durable complete responses. The role and clinical value of HD IL-2 needs to be re-examined and better delineated in this era of emerging targeted therapy and immune checkpoint blockade therapies. This editorial presents a perspective based on recent experience using PROCLAIMSM, a large multicenter retrospective and prospective registry of patients receiving HD IL-2. The data reported confirms the potential for durable survival as first reported for HD IL-2 over two decades ago, and supports further investigation of IL-2 therapy in combination or sequence with immune checkpoint inhibitors.

Cancer Immunotherapy with Interleukin-2—Current Status and Future Developments

High-dose interleukin-2 (HD IL-2) has been in clinical use in the treatment of metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) for over 20 years, and has produced substantial, durable responses in selected patients, resulting in cures in some patients with no ongoing therapy or chronic toxicity. However, use of the drug has remained limited owing to its significant acute toxicities, and the fact that only a minority of selected patients derive a response to treatment. Recent registry data support the use of HD IL-2 as first-line therapy in mRCC and mM, producing major responses for some and thus reducing the requirement for long-term therapy. In addition, an enhanced understanding of the role of IL-2 has led to the development of new therapeutic approaches to maximize the anti-tumor response of IL-2. These strategies include combined treatment with vaccines, antibody treatments to block inhibitory pathways, or adoptive cell transfer of T cells. These data and new approaches have led to continued use of HD IL-2 and may increase the number of patients who derive benefit from this treatment.

Complete metastasectomy after high-dose interleukin-2 (HD IL-2) therapy for melanoma

Meeting abstracts Our aim was to describe our experience with surgery after High-dose Interleukin-2 (HD IL-2) therapy in patients who were eligible for complete metastasectomy after treatment. A retrospective chart review was performed on patients with metastatic melanoma seen at Saint Louis

Feasibility of dc vaccine combined with low dose endoxan and high dose il-2 treatment associated with taurolidine for advanced, multi-resistant melanoma patients.

Meeting abstracts 2014 Dillman and coworkers reported 40% 5-year survival of advanced malignant melanoma (MM) patients treated with a combination of Tumor Vaccine in combination with High dose IL-2 versus 13% of similar patients treated only with High Dose of IL-2 (HD IL-2). In order to improve the