High-dose Interleukin-2 Research Articles

Immune correlates of clinical outcome in melanoma.

Melanoma has long been recognized as a potentially immunogenic tumour, but only recently has it become clear that the reason for this resides in its many ultraviolet (UV)-induced mutations and expression of multiple autoantigens which can be targeted by the immune system. The first successful applications of immune-based treatments included passive immunotherapy using high-dose interleukin (IL)-2 and/or adoptive transfer of natural killer (NK)-cells, as well as active immunotherapy using whole cell-derived or peptide vaccines. In the intervening decades, it has become clear that these approaches can lead to durable responses in stage III/IV melanoma, and even to functional cures - but only in a vanishingly small fraction of patients. With the advent of immune checkpoint blockade first with anti-cytotoxic T-lymphocyte 4 (CTLA-4), then with anti-programmed cell death 1 (PD-1) antibodies, and combinations thereof, the small percentage of responding patients may be increased to half, a major accomplishment in this refractory disease. Improved techniques for identifying mutation-derived neoantigens and thus more sophisticated active immunotherapies, probably combined with checkpoint blockade, currently hold great promise for further increasing the fraction of responding patients. As additional immunomodulatory antibodies and therapies become available, it will be increasingly important to develop diagnostic tools to determine which particular therapy is likely to elicit the best response for the individual patient. Practically speaking, therapy selection and efficacy monitoring on the basis of the results of a blood test would be most desirable. The purpose of this review is to consider the feasibility of identifying 'immune signatures' for predicting responses and determining mechanisms responsible for success or failure of these immunotherapies.

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.

Metastasectomy following incomplete response to high-dose interleukin-2.

To evaluate our experience with metastasectomy following partial response or stable disease after treatment with high-dose interleukin-2 (HD IL-2). A total of 305 patients with metastatic renal cell carcinoma or melanoma treated with HD IL-2 over a 12-year period were reviewed. Age, objective response, and overall survival data were evaluated using standard RECIST criteria and Kaplan-Meier estimates. The average age was 55.3 years (range, 15-85) and 245 (80.3%) patients had melanoma and 60 (19.7%) had renal cell carcinoma. The objective response rate to IL-2 for all patients was 13.6% and median survival was 16.8 months. Complete follow-up data were available for 236 patients with 147 (62.3%) progressing after treatment and 8 (3.3%) with a complete response. Incomplete responses were seen in 81 (34.3%) patients, including 57 (24.2%) patients with stable disease and 24 (10.1%) with partial responses. Of these 81 incomplete responders, 15 (18.5%) underwent subsequent metastasectomy. Patients without surgery had overall survival of 38.2 months and median survival has not yet been reached in those who underwent metastasectomy (P = 0.026). The data support prospective evaluation of metastasectomy following incomplete therapeutic responses to immunotherapy and defines a new role for surgical resection following IL-2 and perhaps other immunotherapy regimens.

386P - The treatment of disseminated skin melanoma with high-dose recombinant interleukin-2 in combination with chemotherapy

386P - The treatment of disseminated skin melanoma with high-dose recombinant interleukin-2 in combination with chemotherapy

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.

Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC gene expression profiles. Consensus clustering showed unstable subtype and principal component analysis (PCA) showed a continuous spectrum both within and between datasets. Considering the lack of discrete delineation and continuous spectrum observed, we developed a continuous quantitative prognosis score (Continuous Linear Enhanced Assessment of RCC, or CLEAR score). Prognostic performance was evaluated in independent cohorts from The Cancer Genome Atlas (TCGA) (n = 414) and EMBL-EBI (n = 53), CLEAR score demonstrated both superior prognostic estimates and inverse correlation with anti-angiogenic tyrosine-kinase inhibition in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score. Multiple somatic mutations (VHL, PBRM1, SETD2, KDM5C, TP53, BAP1, PTEN, MTOR) were associated with the CLEAR score. Application of the CLEAR score to independent expression profiling of intratumoral ccRCC regions demonstrated that average intertumoral heterogeneity exceeded intratumoral expression heterogeneity. Wider investigation of cancer biology using continuous approaches may yield insights into tumor heterogeneity; single cell analysis may provide a key foundation for this approach.

Clinical-Grade–Expanded Regulatory T Cells Prevent Graft-versus-Host Disease While Allowing a Powerful T Cell–Dependent Graft-versus-Leukemia Effect in Murine Models

We developed a good manufacturing practices–compatible expansion protocol to improve number and purity of regulatory T cells (Tregs) available for clinical trials. Six clinical-grade separation procedures were performed, followed by expansion with high-dose interleukin (IL)-2, anti-CD3/anti-CD28 TCR stimulation, and rapamycin for 19 days achieving a median of 8.5-fold (range, 6.25 to 13.7) expansion. FOXP3 expression was stably maintained over the culture period, while the percentage of CD127 was significantly reduced. The in vitro suppression assay showed a strong Mixed Lymphocytes Reaction inhibition. In vitro amplification did not induce any karyotypic modification. To evaluate the graft-versus-host disease (GVHD)/graft-versus-leukemia (GVL) bifunctional axis, expanded Tregs and conventional T cells (Tcons) were tested in NOD/SCID/IL2Rgnull mice injected with primary acute myeloid leukemia (AML) cells, AML cell line, acute lymphoid leukemia Philadelphia cell line, or Burkitt-like lymphoma cell line. All mice that received leukemia cells together with expanded Tregs and Tcons were rescued from leukemia and survived without GVHD, showing that Treg expansion procedure did not compromise GVHD control and the strong Tcon-mediated GVL activity. This report might represent the basis for treating high-risk leukemia and/or relapsed/refractory leukemia patients with high-dose Treg/Tcons.

Abstract 3827: NCI 8628 - A randomized phase II study of Ziv-aflibercept (Z) and high dose Interleukin-2 (IL-2) or IL-2 alone for inoperable stage III or IV melanoma

Abstract Background: IL-2 plays a central role in antitumor immunity. VEGF plays a critical role in angiogenesis and host innate and adaptive immunity. High baseline serum VEGF was associated with non-response to IL-2. Z, a high-affinity soluble decoy VEGF receptor, may deplete VEGF prior to IL-2 to reverse the immunosuppressive impact of VEGF and enhance antitumor T cell response. Methods: NCI8628 was a phase II trial of Z and IL-2 (A) versus IL-2 alone (B) randomized 2:1. Eligible patients (pts): Stage III inoperable or Stage IV melanoma. Up to two prior regimens for metastatic melanoma and stable treated brain metastases were allowed. The primary endpoint was progression-free survival (PFS). Results: A total of 89 pts were enrolled, but 5 who never started study treatment were excluded. Six pts (4 in A and 2 in B) who were treated but withdrew early without a response assessment were considered non-responders in this analysis. Pt and disease characteristics are summarized in Table 1. Median number of IL2 cycles was 3 (A) and 2 (B) and of Z cycles in A was 3 (1 - 31). Median follow up for all alive patients was 19 months. Among 84 treated pts (55 in A and 29 in B), there was significant improvement in PFS in favor of A: median and 95% CI of 6.9 (4.2 - 8.8) months vs 2.1 (1.7 - 4.1), logrank p &amp;lt;0.001. No significant difference in OS: median and 95% CI of 23.1 (14.4 - 35.0) months (A) vs 22.3 (12.6 - NA). Response rate (RECIST) was 22% in A (5CR, 7PR) and 17% in B (5PR). Stable disease or PR or CRwas seen in 69% in A and 48% in B. Adverse events were consistent with the AE profiles of monotherapy with IL2 and Z. Grade 4 events in A included decreased lymphocytes (41 pts) and platelets (6), renal (1), hypophosphatemia (4), hypertension (2) and thromboembolism (1). Table 1Arm A (N=55)Arm B (N=29)Age (median and range)55 (26-73)55 (31-74)GenderFemale2211Male3318Cutaneous primary3616Mucosal54Uveal Unknown6 84 5AJCC StageIII (N3) M1a9 103 5M1b116M1c2515 Conclusions: The combination of Z and IL2 significantly improved PFS over IL2 alone, meeting the study’s primary endpoint. The regimen was relatively safe and manageable. Correlative and mechanistic studies are ongoing. Citation Format: Ahmad A. Tarhini, Paul H. Frankel, Christopher Ruel, Marc S. Ernstoff, Timothy M. Kuzel, Theodore F. Logan, Nikhil I. Khushalani, Hussein A. Tawbi, Kim A. Margolin, Sanjay Awasthi, David F. McDermott, Alice Chen, Primo N. Lara, John M. Kirkwood. NCI 8628 - A randomized phase II study of Ziv-aflibercept (Z) and high dose Interleukin-2 (IL-2) or IL-2 alone for inoperable stage III or IV melanoma [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 3827. doi:10.1158/1538-7445.AM2017-3827

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

Abstract 2671: Antitumor activity of NKTR-214 in combination with pmel-1 ACT in an aggressive murine melanoma model

Abstract The adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific T-cell receptors (TCR) has been shown to induce effective anti-tumor response. However, tumors frequently relapse after an initial response. Another strategy towards stimulating the immune system is the use of high-dose interleukin-2 (IL-2) to target the IL-2 receptor (IL2R), leading to immune cell expansion. However, clinically approved IL-2 expands both tumor-killing CD8+ effector T cells (CD8T) as well as regulatory T cells (Tregs) through binding the IL-2Rβγ and IL-2Rαβγ complexes, respectively. Tregs in the tumor lead to immune suppression, which hampers the antitumoral response. NKTR-214 is a CD122-biased cytokine agonist conjugated with multiple releasable chains of polyethylene glycol and designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand effector CD8+ T and NK cells over Tregs. We used the pmel-1 ACT/B16 melanoma tumor model to test the anti-tumor activity of NKTR-214 and evaluate its effects on tumor-specific TCR transgenic T cells. On Day 0 (D0) C57BL/6 mice were implanted with B16-F10 mouse melanoma cells and lymphodepleted with 500 cGy on D6. On D7, mice were treated with either the combination of ACT (T lymphocytes activated in vitro with 1 μg/ml gp100) plus NKTR-214 (0.8 mg/kg, q9dx3, i.v.) or with C57/B6 T cells plus PBS (vehicle control). The tumors of the vehicle control mice (n=12) rapidly grew to the 1500mm3 endpoint in 12 days post-treatment, versus 35 days for the NKTR-214 group (n=12) with only 1 out of 12 mice reaching endpoint. Bioluminescence imaging was used to visualize the in vivo distribution and tumor-homing of antigen-specific T cells. Interestingly, the reporter T cells were retained in the spleen until D7 and could be seen migrating to the tumor at D9 reaching peak of bioluminescence at day 12, a delayed time point compared to the 5 days usually observed in mice treated with standard IL-2. The signal persisted in the NKTR-214 + ACT group until D20 versus D7 in the vehicle-control animals. These data suggest that NKTR-214 + ACT is well tolerated and provides a robust anti-tumor response in the aggressive B16F10 model. Treatment with NKTR-214 + ACT robustly mobilizes T cells into the tumor where they durably persist. The robust and long-lasting effect of NKTR214 supports its potential use in combination with cell-based therapeutics. Citation Format: Giulia Parisi, Justin Saco, Siwen Hu-Lieskovan, Ruixue Zhang, Paige Krystofinski, Cristina Puig Saus, Deborah H. Charych, Antoni Ribas. Antitumor activity of NKTR-214 in combination with pmel-1 ACT in an aggressive murine melanoma model [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 2671. doi:10.1158/1538-7445.AM2017-2671

Adenoviral production of interleukin-2 at the tumor site removes the need for systemic postconditioning in adoptive cell therapy.

Systemic high dose interleukin-2 (IL-2) postconditioning has long been utilized in boosting the efficacy of T cells in adoptive cell therapy (ACT) of solid tumors. The resulting severe off-target toxicity of these regimens renders local production at the tumor an attractive concept with possible safety gains. We evaluated the efficacy and safety of intratumorally administered IL-2-coding adenoviruses in combination with tumor-infiltrating lymphocyte therapy in syngeneic Syrian hamsters bearing HapT1 pancreatic tumors and with T cell receptor transgenic ACT in B16.OVA melanoma bearing C57BL/6 mice. The models are complementary: hamsters are semi-permissive for human oncolytic adenovirus, whereas detailed immunological analyses are possible in mice. In both models, local production of IL-2 successfully replaced the need for systemic recombinant IL-2 (rIL-2) administration and increased the efficacy of the cell therapy. Furthermore, vectored delivery of IL-2 significantly enhanced the infiltration of CD8+ T cells, M1-like macrophages, and B-cells while systemic rIL-2 increased CD25 + FoxP3+ T cells at the tumor. In contrast with vectored delivery, histopathological analysis of systemic rIL-2-treated animals revealed significant changes in lungs, livers, hearts, spleens, and kidneys. In summary, local IL-2 production results in efficacy and safety gains in the context of ACT. These preclinical assessments provide the rationale for ongoing clinical translation.

Surgical Management of Advanced and Metastatic Renal Cell Carcinoma: A Multidisciplinary Approach.

The past decade has seen a rapid proliferation in the number and types of systemic therapies available for renal cell carcinoma. However, surgery remains an integral component of the therapeutic armamentarium for advanced and metastatic kidney cancer. Cytoreductive surgery followed by adjuvant cytokine-based immunotherapy (predominantly high-dose interleukin 2) has largely given way to systemic-targeted therapies. Metastasectomy also has a role in carefully selected patients. Additionally, neoadjuvant systemic therapy may increase the feasibility of resecting the primary tumor, which may be beneficial for patients with locally advanced or metastatic disease. Several prospective trials examining the role of adjuvant therapy are underway. Lastly, the first immune checkpoint inhibitor was approved for metastatic renal cell carcinoma (mRCC) in 2015, providing a new treatment mechanism and new opportunities for combining systemic therapy with surgery. This review discusses current and historical literature regarding the surgical management of patients with advanced and mRCC and explores approaches for optimizing patient selection.

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 &gt; 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 &gt; 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 &gt; 5 - &lt; 10 yrs after IL2, and 19 RCC and 27 mm are alive &gt; 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 ( &gt; 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.

Adjuvant Therapy for High Risk Localized Kidney Cancer: Emerging Evidence and Future Clinical Trials.

We reviewed the literature on adjuvant therapies for patients with high risk localized kidney cancer following surgical resection. In this analysis we merge 2 recently published prospective trials with conflicting results within the context of their respective designs. In addition, we spotlight upcoming trials that use novel immunotherapy based checkpoint inhibitors and have the potential to establish a new standard of care. We searched PubMed® for English language articles published through January 2017 using the keywords "renal cell carcinoma," "kidney cancer," "immunotherapy," "targeted therapy" and "adjuvant therapy." ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings are also included. Adjuvant therapies for high risk localized kidney cancer can be grouped into the categories of 1) traditional immunotherapy, 2) inhibitors of the vascular endothelial growth factor and mTOR (mammalian target of rapamycin) pathways, 3) vaccines and antibody dependent cytotoxic agents, and 4) immune checkpoint inhibitors. Several trials of traditional immunotherapy, such as interferon-α and high dose interleukin-2, failed to demonstrate benefit as adjuvant treatment and were associated with significant adverse events. Vascular endothelial growth factor and mTOR inhibitors have less severe toxicity in metastatic disease and, therefore, are natural considerations for adjuvant trials. However, current data are conflicting. The ASSURE (Sunitinib Malate or Sorafenib Tosylate in Treating Patients with Kidney Cancer that was Removed by Surgery, NCT00326898) trial found no recurrence-free survival benefit of sorafenib or sunitinib over placebo, while S-TRAC (Clinical Trial Comparing Efficacy and Safety of Sunitinib versus Placebo for the Treatment of Patients at High Risk of Recurrent Renal Cell Cancer, NCT00375674) revealed that 1 year of sunitinib improved recurrence-free survival by 1.2 years. Vaccine based treatments and antibody dependent cytotoxic agents have had mixed results. New trials evaluating immune checkpoint inhibitors are planned, given the impressive efficacy and tolerability as second line agents in metastatic disease. Future adjuvant trials are likely to be guided by molecular signatures to treat patients most likely to benefit. Based on the available data, there appears to be no role for traditional immunotherapy as adjuvant treatment in patients with high risk localized kidney cancer following surgical resection. S-TRAC provides evidence that 1 year of adjuvant sunitinib in patients with higher risk locoregional disease increases the median time to recurrence. However, the data on overall survival are immature and adverse effects are common. Results from trials investigating immune checkpoint inhibitors are highly anticipated.

Results of two sequential phase II studies of interleukin-2 (IL2) in metastatic renal cell carcinoma and melanoma: high-dose continuous intravenous IL2 infusion and subcutaneous IL2 administration in combination with alpha interferon

The results of two sequential trials, the first one with high dose interleukin 2 (IL2) by continuous intravenous infusion and the second one with subcutaneous IL2 and alpha-interferon (alpha IFN), performed in consecutive patients with metastatic melanoma and renal carcinoma at the Clinica Universitaria de Navarra are presented. In the high-dose continuous IL2 trial, recombinant IL2, 18 x 10(6) IU/m2, was administered daily by continuous infusion five days a week for two weeks, and the treatment cycle was repeated after a rest of 2 weeks. Twenty two patients were treated and objective responses were observed in 3 (13.3%). Toxicity was frequent and severe, and all but one required dose reduction. The mortality rate was 9% (2/22). In the subcutaneous IL2 and alpha IFN trial, subcutaneous IL2, 4.8 x 10(6) IU/m2, was administered daily, five days a week, for 3 consecutive weeks. IL2 dose was given every 8 hours on the first day and every 12 hours on the second day, as a loading induction dose. Concomitant alpha-IFN, 3 x 10(6) IU/m2 was given subcutaneously once a day on days 1, 3 and 5 weekly each week for the duration of IL2 therapy. Of the 24 patients treated with this combination, 3 partial responses were noticed (12.5%) and the toxicity was mild to moderate. These results suggest that both, IL2 alone or IL2 in combination with alpha-IFN are minimally active and that any improvement in tolerance might impair its antitumor activity.

Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study

Uveal melanoma is a rare tumour with no established treatments once metastases develop. Although a variety of immune-based therapies have shown efficacy in metastatic cutaneous melanoma, their use in ocular variants has been disappointing. Recently, adoptive T-cell therapy has shown salvage responses in multiple refractory solid tumours. Thus, we sought to determine if adoptive transfer of autologous tumour-infiltrating lymphocytes (TILs) could mediate regression of metastatic uveal melanoma. In this ongoing single-centre, two-stage, phase 2, single-arm trial, patients (aged ≥16 years) with histologically confirmed metastatic ocular melanoma were enrolled. Key eligibility criteria were an Eastern Cooperative Oncology Group performance status of 0 or 1, progressive metastatic disease, and adequate haematological, renal, and hepatic function. Metastasectomies were done to procure tumour tissue to generate autologous TIL cultures, which then underwent large scale ex-vivo expansion. Patients were treated with lymphodepleting conditioning chemotherapy (intravenous cyclophosphamide [60 mg/kg] daily for 2 days followed by fludarabine [25 mg/m2] daily for 5 days, followed by a single intravenous infusion of autologous TILs and high-dose interleukin-2 [720 000 IU/kg] every 8 h). The primary endpoint was objective tumour response in evaluable patients per protocol using Response to Evaluation Criteria in Solid Tumors, version 1.0. An interim analysis of this trial is reported here. The trial is registered at ClinicalTrials.gov, number NCT01814046. From the completed first stage and ongoing expansion stage of this trial, a total of 21 consecutive patients with metastatic uveal melanoma were enrolled between June 7, 2013, and Sept 9, 2016, and received TIL therapy. Seven (35%, 95% CI 16-59) of 20 evaluable patients had objective tumour regression. Among the responders, six patients achieved a partial response, two of which are ongoing and have not reached maximum response. One patient achieved complete response of numerous hepatic metastases, currently ongoing at 21 months post therapy. Three of the responders were refractory to previous immune checkpoint blockade. Common grade 3 or worse toxic effects were related to the lymphodepleting chemotherapy regimen and included lymphopenia, neutropenia, and thrombocytopenia (21 [100%] patients for each toxicity); anaemia (14 [67%] patients); and infection (six [29%] patients). There was one treatment-related death secondary to sepsis-induced multiorgan failure. To our knowledge, this is the first report describing adoptive transfer of autologous TILs to mediate objective tumour regression in patients with metastatic uveal melanoma. These initial results challenge the belief that metastatic uveal melanoma is immunotherapy resistant and support the further investigation of immune-based therapies for this cancer. Refinement of this T-cell therapy is crucial to improve the frequency of clinical responses and the general applicability of this treatment modality. Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

High-Dose Interleukin-2: Evaluation of a Standardized Order Set for Biotherapy in an Intensive Care Unit

Life-threatening toxicity may result from administration of high-dose (HD) interleukin-2 (IL-2). Patients receiving HD IL-2 treatment often experience severe adverse side effects, which result in the interruption of treatment. . A standardized order set (SOS) was developed for patients with melanoma or renal cell carcinoma receiving HD IL-2. The aims of the study were to determine compliance of clinicians to the SOS, report the completed doses and major side effects of HD IL-2, and document the satisfaction level of clinicians. . A retrospective chart review of 40 health records of patients with melanoma or renal cell carcinoma who were treated with HD IL-2 was conducted to determine compliance to the SOS. Staff satisfaction with the SOS was surveyed. . The SOS was successfully implemented with a provider compliance rate of 90%. Cardiovascular side effects were the most common. Clinicians found the SOS very satisfactory or superior in guiding care and treatment of side effects.

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.

The impact of checkpoint blockade prior to adoptive cell therapy using tumor-infiltrating lymphocytes for metastatic melanoma: An update from MD Anderson Cancer Center.

138 Background: Adoptive cell therapy (ACT) of autologous tumor-infiltrating lymphocytes (TIL) can produce long lasting treatment responses in patients (pts) with metastatic melanoma. In our initial report of 31 treated pts, we demonstrated overall response rate (ORR) of 48%. Due to the evolution of treatment options for metastatic melanoma with heavy reliance on immunomodulatory therapies, we sought to re-evaluate responses in the era of checkpoint blockade. Methods: Pts receive treatment consisting of 7 days of lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine. High dose interleukin-2 (720,000 IU/kg IV q 8 hrs up to 15 doses) was infused after TIL infusion. Responses were assessed by imaging per irRC. Results: A total of 74 pts have been treated in our initial TIL study with an updated ORR assessment of 43%. Stratification of pts according to their checkpoint blockade immune-modulator therapy prior to TIL ACT, demonstrated that prior Ipilimumab (Ipi) decreased ORR to 33% compared to 51% in checkpoint naïve pts and decreased overall survival (OS) post-TIL therapy (median 7.7 vs 24.6 months respectively). There were too few pts to assess the impact of anti-PD1 as a single agent. A multiparametric analysis revealed that LDH levels at the time of therapy mainly influences OS and ORR to TIL but still could not invalidate the impact of Ipi prior to TIL ACT. The durability of the response was also found to be different between the 2 groups (30% for Ipi prior and 50% No Ipi prior). This new reality also impacted previously reported parameters that correlated with ORR to TIL ACT such as the expression of B-and-T lymphocyte attenuator (BTLA) on CD8+ TIL. Interestingly, assessment of mutation load (ML) of the tumors prior to TIL ACT showed that the check point naïve group display a high ML ( &gt; 100) within their tumor whereas some patients who had Ipi prior to TIL have a low ML ( &lt; 100). Conclusions: Our preliminary analysis shows that pre-treatment with Ipi decreases ORR to TIL ACT. Understanding how prior ipi modifies TIL, the tumor and microenvironment will help to define the full extent of the impact and how to best treat Ipi refractory pts with TIL. Clinical trial information: NCT00338377.

Targeting of IL-2 to cytotoxic lymphocytes as an improved method of cytokine-driven immunotherapy

ABSTRACTThe use of high-dose interleukin-2 (IL-2) has fallen out of favor due to severe life-threatening side effects. We have recently described a unique way of directly targeting IL-2 to cytotoxic lymphocytes using a virally encoded immune evasion protein and an IL-2 mutant that avoids off-target side effects such as activation of regulatory T cells and vascular endothelium.