Courses Of Interleukin-2 Research Articles

Tumor-infiltrating lymphocytes: A new hope

Tumor-infiltrating lymphocytes (TILs) can be massively expanded from resected tumors and used as a cellular treatment for advanced malignancies. TILs require a preparative non-myeloablative chemotherapy followed by an abbreviated course of interleukin-2. Here, we review the historical development of TIL therapy and discuss potential solutions to ongoing roadblocks that may result in broader and improved efficacy for patients afflicted with treatment-refractory, advanced cancer.

Dynamics of circulating cytokines and chemokines during and after tumor-infiltrating lymphocyte cell therapy with lifileucel in advanced melanoma patients.

9594 Background: Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, has demonstrated potentially clinically meaningful activity and durable responses in patients with advanced (unresectable or metastatic) melanoma. The regimen includes nonmyeloablative lymphodepletion (NMA-LD) prior to lifileucel infusion, and a short course of interleukin-2 (IL-2) post infusion. The safety profile of the regimen is consistent with the underlying disease and the known safety profiles of NMA-LD and IL-2. Cytokine release syndrome (CRS) is an acute and severe adverse event commonly associated with chimeric antigen receptor T-cell therapy. Here, we report circulating cytokine levels during and after the lifileucel treatment to monitor immune activation, and the dynamics of cytokines and chemokines to explore mechanism of action and potential predictive clinical biomarkers. Methods: The full analysis set of C-144-01 (NCT02360579) includes 153 patients with unresectable or metastatic melanoma who have progressed on checkpoint inhibitors and, if applicable, BRAF/MEK inhibitors. After tumor resection, patients received NMA-LD (cyclophosphamide on Days −7 to −6 and fludarabine on Days −5 to −1) followed by a single lifileucel infusion (Day 0) and up to 6 doses of IL-2 (Days 0-4). Peripheral blood samples were collected at baseline (pre-NMA-LD and pre-lifileucel infusion) and post-lifileucel infusion on Days 1, 4, 14, 42, and 84. Serum cytokine and chemokine levels were measured with BioPlex and included a multiplex panel for IL-6, IL-7, IL-9, IL-10, IL-12, CCL2, CXCL10, IFN-γ, and TNF-α. Plasma samples also were tested for IL-6, IL-15, and IL-7 levels by ELISA. Results: IL-15 levels following NMA-LD peaked at Day 1 and returned to baseline by Day 42. This is consistent with prior reports that NMA-LD increases circulating IL-15 levels, which may promote TIL expansion in the absence of competing endogenous lymphocytes. Similarly, IL-7 and CCL2 also peaked at Day 1. IL-6 did not increase during or after the lifileucel regimen, consistent with absence of severe systemic inflammation including higher grade CRS after lifileucel treatment. There was no difference in cytokine and chemokine levels between responders and nonresponders in the full analysis set. Conclusions: These data support the hypothesized mechanism of action of NMA-LD in the lifileucel regimen. Cytokine levels measured during treatment are consistent with lack of severe systemic inflammation observed in patients treated with lifileucel. Cytokine and chemokine dynamics did not predict for response to lifileucel. Clinical trial information: NCT02360579 .

Maintenance Therapy With Interleukin-2 for Childhood AML: Results of ELAM02 Phase III Randomized Trial.

Despite significant progress in the treatment of pediatric acute myeloblastic leukemia (AML), relapse remains the commonest cause of death. Randomized ELAM02 trial questioned if maintenance therapy with interleukin-2 (IL2), for 1 year, improves disease-free survival (DFS). Patients aged 0 to 18 years, with newly diagnosed AML (excluding patients with acute promyelocytic leukemia or down syndrome AML) were enrolled. They received 1 course of induction treatment (cytarabine and mitoxantrone) and 3 courses of consolidation treatment (high-dose cytarabine in courses 1 and 3). According to the cytogenetics risk, patients not undergoing hematopoietic stem cell transplantation, still in complete remission (CR) after the third course of consolidation treatment, were eligible for randomization to 1 year of maintenance therapy with monthly courses of IL2 or no maintenance treatment. There were 438 evaluable patients, 154 of whom were randomized to the IL2/no maintenance groups. Relapse occurred in 28 patients from the IL2+ group and 29 patients in the IL2- group. Survival was similar in the 2 groups, with a 4-year DFS of 62% without IL2 and 66% with IL2 (P = 0.75). In the CBF population, 4-year DFS was 55% without IL2 and 78% with IL2 (P = 0.07). No deaths from toxicity or excess of serious adverse events related to IL2 treatment were recorded. Prolonged IL2 for maintenance therapy after intensive chemotherapy is feasible and safe in pediatric AML patients in their first CR. Such treatment did not improve DFS in this study, but a positive trend was observed in favor of IL2 maintenance therapy among core binding factor acute myeloblastic leukemia.

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 > 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 > 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.

Relevance of a One-Year Maintenance Therapy with Interleukin-2 in the Treatment of Childhood Acute Myeloid Leukemia: Results from the French Multicenter, Phase III, Randomized Controlled Sfce Trial, ELAM02

▪Background: Childhood acute myeloid leukemia (AML) remains a challenging disease as the outcome is still poor despite major improvement over the past decades; current survival rates are around 70% but event free survival (EFS) is only about 50%. No benefit of standard maintenance chemotherapy has been proven after intensive induction/consolidation chemotherapy.Objective: To determine whether the addition of a one-year maintenance therapy using interleukin-2 (IL-2), known to stimulate antitumor immunity, decreases the risk of relapse and improves EFS in pediatric AML.Methods: ELAM02 trial was designed to recruit patients aged from 0 to 18 years, diagnosed with primary AML. Children with acute promyelocytic leukemia and Down Syndrome were not included. The treatment consisted of one induction course (cytarabine and mitoxantrone) and three consolidation courses (course 1 and 3 with high dose cytarabine); all children without t(8;21) were candidates for hematopoietic stem cell transplant (HSCT) in complete remission (CR) after 1 to 2 courses of consolidation if a geno-identical donor was available; children with poor-prognosis karyotype were also candidates for HSCT with pheno-identical donor.The patients not receiving HSCT and in continuous CR after the third course of consolidation were eligible for randomization for a one-year maintenance therapy consisting in monthly courses of IL-2. IL-2 (Proleukin®, Chiron, Novartis) was given subcutaneously at 2.5 MUI/m² on day 1 and at 5 MUI/m² from day 2 to 5. Cycles were planned to be given monthly for up to 12 cycles. In case of side effects such as severe (grade ≥ 3) clinical toxicities (fever >40°C, hypotension requiring IV fluids) and/or severe biological toxicities (thrombocytopenia (grade ≥ 3), renal dysfunction (grade ≥ 2), liver dysfunction (grade ≥ 3)) doses of IL-2 was lowered of 50%. In case of persistent side effects, treatment was discontinued. The control group received no maintenance treatment.Results: The 28 French SFCE centers participated to the study, leading to the enrollment of 441 patients from March 2005 to December 2011. Among the 441 enrolled patients, 3 patients were excluded due to non-conformity of inclusion criteria; 392/438 (89%) were in CR after the first consolidation course and 116 (30%) were allografted in CR1. Out of the 241 eligible patients for randomization, i.e. still in CR after the third course of consolidation, 154 (64%) were actually randomized for maintenance therapy; causes for non-randomization were either parents refusal (n=50, 21%) or medical decision (n=37, 15%). Median follow-up is 5 years. The characteristics of the randomized patients at diagnosis were as follows: [Display omitted] Median number of IL-2 cycles administered was 12 [5-12], the mean being 8.6 ± 4.2. Among the 77 patients receiving maintenance therapy, IL-2 was stopped before cycle 6 in 20 patients (26%) and after cycle 6 in 18 (23%); 39 patients (51%) received 12 cycles. Treatment was stopped because of relapse occurrence (n=15), severe persistent toxicities (n=6) or parents or medical decision (n=17). The most frequent toxicities related to IL-2 treatment were fever, chills, and cytolytic hepatitis; no toxic death related to IL-2 therapy was observed. Incidence of relapses in IL2+ group and IL2- group were 36% (n=28) and 38% (n=29) respectively. The 5-year disease free survival (DFS) was 62 % (95% CI 51-73) for the IL2- group vs. 64% (95% CI 53-75) for the IL2+ group (p=0.74). Among the CBF population, a trend in favor of the IL-2 treatment was observed as the 5-year DFS was 57% (95% CI 43-71) for the IL2- group vs. 78% (95% CI 63-94) for the IL-2+ group (p=0.08).Conclusion: A prolonged administration of IL-2 as maintenance therapy after intensive chemotherapy is feasible in pediatric AML patients in first CR but did not improve DFS in this study. DisclosuresNo relevant conflicts of interest to declare.

Low-Dose Interleukin-2 Therapy: Effects in Chronic Renal Allograft Dysfunction.

Immune modulating therapies gain increasing importance in treatment of patients with autoimmune diseases and organ transplantation. Daily low-dose interleukin-2 therapy has been shown to expand regulatory T-cells with clinical improvement in patients with HCV-induced vasculitis or chronic graft-versus-host disease. Here, we studied safety, immunologic effects, and impact on chronic allograft dysfunction of the administration of low-dose interleukin-2 in kidney transplant recipients (KTRs) with end-stage allograft dysfunction. 3 KTRs with chronic renal allograft dysfunction who were refractory to conventional therapy, and who were receiving triple-drug maintenance immunosuppression, received one course of interleukin-2 (1.5 million IU per day) for 5 days, followed by repetition at week 3. Safety and effectiveness of the treatment were evaluated by monitoring lymphocyte subpopulations, gene expression profiles of 13 selected tolerance-associated genes, and the development of HLA- and non-HLA-antibodies. CMV-specific, BKV-specific and alloreactive T-cells were measured using an interferon-γ Elispot assay. No serious adverse events were observed. Interleukin-2 therapy didn't induce effector T-cell activation, acute cellular or antibody-medicated rejection, or reactivation of latent viruses as CMV or BKV. We observed an improvement of allograft function in all KTRs after 2 courses of interleukin-2 with a reduction of serum creatinine levels from 4.37 to 3.35, 4.44 to 3.39, and 2.88 to 2.09mg/dl. However, all KTRs showed a return to baseline serum creatinine levels after discontinuation of interleukin-2 therapy. Administration of low-dose interleukin-2 was followed by an increase in the percentage of CD4+CD25+FOXP3+ Tregs [maximum value ÷ baseline value × 100 = 350%]. Low-dose IL-2 had minimal effects on other T-cell subpopulations, NK-cells, or B-cells. Gene expression patterns of FOXP3 and MAN1a1 were upregulated by interleukin-2 therapy. Low-dose interleukin-2 therapy was safe and led to expansion of regulatory T-cells and temporary improvement of allograft function in KTRs with chronic renal allograft dysfunction.

Modeling interleukin-2-based immunotherapy in AIDS pathogenesis

In this paper, we sought to identify the CD4+ T-cell dynamics in the course of HIV infection in response to continuous and intermittent intravenous courses of interleukin-2 (IL-2), the principal cytokine responsible for progression of CD4+ T-lymphocytes from the G1 to the S phase of the cell cycle. Based on multivariate regression models, previous literature has concluded that the increase in survival of CD4+ T-cell appears to be the critical mechanism leading to sustained CD4+ T-cell levels in HIV-infected patients receiving intermittent IL-2 therapy. Underscored by comprehensive mathematical modeling, a major finding of the present work is related to the fact that, rather than due to any increase in survival of CD4+ T-cells, the expressive, selective and sustained CD4+ T-cell expansions following IL-2 administration may be related to the role of IL-2 in modulating the dynamics of Fas-dependent apoptotic pathways, such as activation-induced cell death (AICD) or HIV-specific apoptotic routes triggered by viral proteins.

Regulatory T-Cell Responses to Low-Dose Interleukin-2 in HCV-Induced Vasculitis

Patients with vasculitis induced by the hepatitis C virus (HCV) have reduced levels of regulatory T cells (Tregs). Resolution of HCV infection correlates with cure of vasculitis and the recovery of Treg levels. We reasoned that interleukin-2, a cytokine that promotes Treg survival and function, could be beneficial for patients with vasculitis that is resistant to HCV therapy. We investigated the safety and immunologic effects of the administration of low-dose interleukin-2 in a prospective open-label, phase 1-phase 2a study. Ten patients with HCV-induced vasculitis that was refractory to conventional antiviral therapy, rituximab therapy, or both and who were not receiving glucocorticoid or immunosuppressant therapy, received one course of interleukin-2 (1.5 million IU per day) for 5 days, followed by three 5-day courses of 3 million IU per day at weeks 3, 6, and 9. Both the safety of the treatment and its effectiveness were evaluated, the latter by monitoring the Treg response and the clinical signs of HCV vasculitis. No adverse events reached a level higher than grade 1. The treatment did not induce effector T-cell activation, vasculitis flare, or increased HCV viremia. We observed a reduction in cryoglobulinemia in 9 of 10 patients and improvement of vasculitis in 8 of 10. Administration of low-dose interleukin-2 was followed by an increase in the percentage of CD4+, CD25(high), forkhead box P3 (FOXP3+) Tregs [E(max) (maximum value)÷baseline value×100=420%] with potent suppressive activity in all subjects and by a concomitantly decreased proportion of marginal-zone B cells. Transcriptome studies of peripheral-blood mononuclear cells revealed that interleukin-2 induced a global attenuation of the signatures for inflammation and oxidative stress mediators. The trial showed that low-dose interleukin-2 was not associated with adverse effects and led to Treg recovery and concomitant clinical improvement in patients with HCV-induced vasculitis, an autoimmune condition. (Funded by the French Agency for Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT00574652.).

Colonic pneumatosis and intestinal perforations with sunitinib treatment for renal cell carcinoma

Keywords Pneumatosis.Intestinalperforations.Sunitinibtreatment.RenalcellcarcinomaCase historiesPatient 1 A woman with renal cell carcinoma (RCC)presented with sudden right sided flank pain and anuria.Two years earlier she was diagnosed with RCC clear celltype and had a left-sided nephrectomy performed at thattime. Her initial staging evaluation revealed multiplepulmonary nodules consistent with metastatic disease andshe was started on sorafenib therapy. She remained on thistherapy for 9 months, but was then found to haveprogressive disease and high-dose interleukin-2 (IL2) wasinitiated. The patient developed bilateral pulmonary edemaduring her initial course of IL2 which was believed to besecondary to IL2-induced capillary leak and requiredendotracheal intubation. Accordingly, IL2 was abandonedwithout completing a full course and treatment withsunitinib (50 mg daily for 4 weeks followed by a 2 weekbreak) was pursued.Thirteen months after starting sunitinib, the patientdescribed approximately 12 h of acute right-sided flankpain with no urine output over that time period. Her pasthistory included a tiny calculus in the right kidney. Shedenied vomiting, diarrhea or recent change in her bowelmovements. Laboratory analysis revealed a lactate of3.5 mmol/l (normal range 0.5–2.2 mmol/l). A computedtomography (CT) exam of the abdomen and pelvis wasordered, showing colonic pneumatosis on the right andpneumoretroperitoneum (Fig. 1a–d). The patient proceededto surgery, with placement of a ureteral stent and a right-sided hemi-colectomy. Cystoscopy and an intraoperativeretrograde ureteropyelogram did not demonstrate an ob-structive stone and the anuria was attributed to gastrointes-tinal perforation (GIP). Pathologic examination of the rightcolon showed extensive pneumatosis cystoides intestinalis(Fig. 1e) and focal areas of ulceration of the mucosa withtransmural acute and chronic inflammation and giant cellreaction (Fig. 1f); microthrombi were observed in thevessels of the lamina propria. Three regional lymph nodes

Urticaria and Angioedema in Renal Cell Cancer Patients Treated with IL-2

Interleukin-2 therapy has produced significant improvement in a proportion of patients with renal cell cancer. Dermatologic side effects, such as erythema, have been very common. However, we could find only 2 reports of urticaria in the medical literature.Here, we report 8 patients with renal cell cancer who developed urticaria in association with interleukin-2 therapy. The hives tended to occur at the end of a treatment cycle. Skin tests with IL-2 were negative in two patients. Urticaria did not worsen or consistently occur with repeated courses of interleukin-2 and anaphylaxis was not observed in any patient. Six of the 8 patients previously had urticaria unrelated to IL-2 therapy.

Interleukin-2 given to asymptomatic HIV-infected individuals leads to an exaggerated response of the pituitary gland to the action of CRH.

Studies investigating the impact of interleukin-2 (IL-2) on the corticotroph axis have shown that IL-2 can stimulate cortisol and ACTH secretion. However, the site, the time course and the mechanisms of IL-2 stimulation of the corticotroph axis are still not known. The aim of this study was to gain insight into the mechanisms of IL-2 stimulation of the corticotroph axis. A total of 9 x 10(6) IU/day IL-2 were given to 18 male HIV-infected patients treated with a combination of HIV antiviral drugs (usually two reverse-transcriptase inhibitors and one protease-inhibitor) over a course of 4-5 days. Seven of these 18 patients received a second course of IL-2. Cortisol levels increased significantly (P < 0.001) from baseline levels (427 +/- 118 nmol/l) to 746 +/- 132 nmol/l after 4 days of IL-2 therapy with a gradual decrease to baseline within 10 days after the end of therapy. ACTH showed a similar pattern rising from 5.9 +/- 1.9 pmol/l at baseline to 12.4 +/- 4.6 pmol/l on day 4 (P < 0.001). The cortisol response after CRH application (carried out at 15.00 h) was significantly more pronounced at the end of IL-2 application (CRH test B, baseline: 330 +/- 59 nmol/l, peak 774 +/- 134 nmol/l, 135% increase) when compared to pretreatment (CRH test A, baseline: 226 +/- 73 nmol/l, peak 459 +/- 103 nmol/l, 103% increase, P </= 0.0001). The cortisol response 9 days after the end of IL-2 administration showed a similar pattern when compared to pretreatment values. The ACTH response after CRH was essentially paralleled by the cortisol response (CRH test B, baseline: 6.1 +/- 2.8 pmol/l, peak 16.0 +/- 4.4 pmol/l, 170% increase; CRH test A, baseline: 4.3 +/- 1.9 pmol/l, peak 9.2 +/- 3.1 pmol/l, 110% increase, P = 0.0005). Furthermore, we observed higher ACTH and cortisol concentrations in the morning when compared to late afternoon values during treatment with IL-2 [cortisol: baseline: 426 +/- 73 nmol/l (8.00 h); 226 +/- 73 nmol/l (15.00 h)]; day 4: [746 +/- 132 nmol/l (8.00 h); 339 +/- 59 nmol/l (15.00 h)]; ACTH: baseline: [5.9 +/- 1.9 pmol/l (8.00 h); 4.3 +/- 1.9 pmol/l (15.00 h)]; day 4: [12.4 +/- 4.7 pmol/l (8.00 h); 6.1 +/- 2.8 pmol/l (15.00 h)]. The data from this in vivo study suggest that IL-2 most likely resulted in corticotroph hyperplasia leading to an exaggerated response of the pituitary gland to the action of CRH.

Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) has led to significant changes in mortality and morbidity in the human immunodeficiency virus type 1 (HIV-1) epidemic. Nevertheless, because of molecular mechanisms of viral persistence, HAART does not eradicate HIV-1. Didanosine and hydroxyurea were added to the antiretroviral regimens of 3 HIV-1-infected men who were receiving stable HAART and who had HIV-1 RNA levels <50 copies/mL at the initiation of the study protocol, as a novel intensification to attack cryptic viral replication; low-dose OKT3 was then administered, followed by a course of interleukin-2, to stimulate latent provirus. Replication-competent virus was undetectable after treatment, and plasma viral RNA was either undetectable or <5 copies/mL. In trial periods during which no antiretroviral therapy was administered, the patients developed plasma viral rebound. This translational approach combines novel intensification and stimulation therapy to deplete residual HIV-1 reservoirs. Additional experimental approaches must be developed if HIV-1 eradication is to become possible in patients receiving virally suppressive HAART.

The HYDILE Trial: Efficacy and Tolerance of a Quadruple Combination of Reverse Transcriptase Inhibitors Versus the Same Regimen Plus Hydroxyurea or Hydroxyurea and Interleukin-2 in HIV-Infected Patients Failing Protease Inhibitor-Based Combinations

Purpose: To compare the efficacy and tolerance of a stavudine (d4T), didanosine (ddI), efavirenz (EFV), and abacavir (ABC) combination regimen with an identical regimen plus hydroxyurea (HU), or plus HU and interleukin-2 (IL-2), in patients failing protease inhibitor-based combinations and naive of EFV and ABC. Method: This was a randomized prospective trial in 69 HIV-infected patients recruited in one clinical center. Antiretroviral drugs were administered at standard doses according to weight. HU was added at week 6 at 500 mg twice daily. Three courses of IL-2 were given subcutaneously at 4.5 MU twice daily for 5 consecutive days, between weeks 24 and 40. The proportion of patients reaching plasma HIV-1 RNA <200 and <50 copies/mL was compared in the three trial groups at weeks 6, 24, and 48 using intent-to-treat and as-treated analyses. CD4+ T-cell count changes from baseline were also assessed at the same time points, along with anthropometric and metabolic measurements. Results: After 48 weeks, only 25% of patients receiving antiretrovirals had plasma HIV-1 RNA <200 copies/mL versus 59.1% in the group receiving HU and 56.5% in the group receiving HU and IL-2 (intent-to-treat; p < .01). At the 50 copies/mL cutoff, the results were 20.8%, 54.5%, and 47.8%, respectively. Most treatment discontinuations were due to failure in the first group and adverse events in the two others. A median decline of 27 CD4+ cells was observed in patients receiving antiretrovirals plus HU, against a gain of 78-118 cells at week 48 in patients receiving antiretrovirals alone or in combination with HU and IL-2. More patients were affected by clinical fat atrophy symptoms at week 48 than at baseline. Additionally, a trend toward increased cholesterol levels was observed throughout the study. Conclusion: During this trial, virologic response in patients failing previous regimens was clearly enhanced by the addition of HU, despite d4T and ddI recycling. Although adverse events were more frequent in the HU-containing arms, no unexpected toxicity was observed and the blunted CD4 response prompted by HU was corrected by the addition of IL-2. The combination of HU with reverse transcriptase inhibitors can therefore be regarded as a valuable alternative for patients with few remaining therapeutic options.

The HYDILE Trial: Efficacy and Tolerance of a Quadruple Combination of Reverse Transcriptase Inhibitors Versus the Same Regimen Plus Hydroxyurea or Hydroxyurea and Interleukin-2 in HIV-Infected Patients Failing Protease Inhibitor-Based Combinations

Purpose: To compare the efficacy and tolerance of a stavudine (d4T), didanosine (ddI), efavirenz (EFV), and abacavir (ABC) combination regimen with an identical regimen plus hydroxyurea (HU), or plus HU and interleukin-2 (IL-2), in patients failing protease inhibitor-based combinations and naive of EFV and ABC. Method: This was a randomized prospective trial in 69 HIV-infected patients recruited in one clinical center. Antiretroviral drugs were administered at standard doses according to weight. HU was added at week 6 at 500 mg twice daily. Three courses of IL-2 were given subcutaneously at 4.5 MU twice daily for 5 consecutive days, between weeks 24 and 40. The proportion of patients reaching plasma HIV-1 RNA <200 and <50 copies/mL was compared in the three trial groups at weeks 6, 24, and 48 using intent-to-treat and as-treated analyses. CD4+ T-cell count changes from baseline were also assessed at the same time points, along with anthropometric and metabolic measurements. Results: After 48 weeks, only 25% of patients receiving antiretrovirals had plasma HIV-1 RNA <200 copies/mL versus 59.1% in the group receiving HU and 56.5% in the group receiving HU and IL-2 (intent-to-treat; p < .01). At the 50 copies/mL cutoff, the results were 20.8%, 54.5%, and 47.8%, respectively. Most treatment discontinuations were due to failure in the first group and adverse events in the two others. A median decline of 27 CD4+ cells was observed in patients receiving antiretrovirals plus HU, against a gain of 78-118 cells at week 48 in patients receiving antiretrovirals alone or in combination with HU and IL-2. More patients were affected by clinical fat atrophy symptoms at week 48 than at baseline. Additionally, a trend toward increased cholesterol levels was observed throughout the study. Conclusion: During this trial, virologic response in patients failing previous regimens was clearly enhanced by the addition of HU, despite d4T and ddI recycling. Although adverse events were more frequent in the HU-containing arms, no unexpected toxicity was observed and the blunted CD4 response prompted by HU was corrected by the addition of IL-2. The combination of HU with reverse transcriptase inhibitors can therefore be regarded as a valuable alternative for patients with few remaining therapeutic options.

Interleukin-2 and 13-cis retinoic acid in the treatment of minimal residual disease: A phase II study

Interleukin-2 (IL-2) which has no cross-resistance with chemotherapy, has given responses in tumors resistant to chemotherapy, and shown to be more effective when tumor burden is low. 13-cis retinoic acid (RA) has immunomodulatory properties, potentially synergistic with IL-2. The objective of this pilot phase II study was to verify the immunomodulatory properties, activity and toxicity of outpatient immunotherapy with subcutaneous low dose IL-2 and oral RA, identified in a previous phase-I study, in patients with advanced solid cancer in whom a response or stable disease as a result of standard chemotherapy had been achieved. Eighty patients with advanced solid tumors after standard chemotherapy, were treated with IL-2: 1.8 x 106 IU and RA: 0.5 mg/kg for 5 days/week for 2 consecutive cycles of 3 weeks, with a 1-week rest, for up to 1 year. A total of 511 courses of IL-2/RA therapy were administered (median 6.4 per patient). Tumor markers, T4/T8 ratio and NK were monitored every 2 months. Response evaluation was carried out every 4 months. After a median follow-up time of 31 months there was a statistically significant improvement in the number of total lymphocytes, T4/T8 ratio and NK after IL-2 and RA therapy. Responses and disease stabilization were maintained for a median time of 19.3 months. Six patients were converted from partial to complete response, while 5 patients progressed. Median survival time was not reached yet. Grade 2 cutaneous toxicity and fever were observed in 29 and 13% of patients, respectively. These preliminary data show that after chemotherapy the administration of low-dose subcutaneous IL-2 and oral RA is feasible and has low toxicity. A sustained increase in the immunological parameters known to be prognostically relevant was observed and a clear benefit on tumor response from immunotherapy was obtained in 7.5% of patients.

Safety, pharmacokinetics, and pharmacodynamics of single doses of an oral p38 MAP kinase inhibitor (BIRB 796 BS) in healthy human males a placebo-controlled, randomised study, double blinded at each dose level

Safety, pharmacokinetics, and pharmacodynamics of single doses of an oral p38 MAP kinase inhibitor (BIRB 796 BS) in healthy human males a placebo-controlled, randomised study, double blinded at each dose level

An IL-2/Ig Fusion Protein Influences CD4+T Lymphocytes in Naive and Simian Immunodeficiency Virus-Infected Rhesus Monkeys

The T cell-stimulatory cytokine interleukin 2 (IL-2) is being evaluated as a therapeutic in the clinical settings of HIV infection and cancer. However, the clinical utility of IL-2 may be mitigated by its short in vivo half-life, toxic effects, and high production costs. We show here that an IL-2/Ig fusion protein possesses IL-2 immunostimulatory activity in vitro and a long in vivo half-life. IL-2/Ig treatment of healthy rhesus monkeys induced significant increases in CD4(+) T lymphocyte counts and expression of CD25 by these cells. Short courses of IL-2/Ig treatment of simian immunodeficiency virus (SIV)-infected rhesus monkeys in conjunction with antiretroviral drugs resulted in increased CD25 expression on T lymphocytes, and transient increases in CD4(+) T lymphocyte counts. Plasma viremia did not increase in these treated animals. Treatment of healthy or SIV-infected rhesus monkeys with a plasmid encoding the IL-2/Ig protein did not affect CD4(+) T lymphocytes. These results demonstrate that IL-2/Ig has potential utility as an immunostimulatory therapeutic.

Impact of the number of treatment courses on the clinical response of patients who receive high-dose bolus interleukin-2.

To determine the impact of treatment with successive courses of high-dose bolus interleukin-2 (IL-2) on the incidence of clinical responses in patients with metastatic melanoma or renal cell cancer. A consecutive series of 350 patients with either metastatic melanoma or renal cell cancer who were treated with high-dose bolus IL-2 in the Surgery Branch, National Cancer Institute, between September 1985 and November 1996 was analyzed, with a median potential follow-up of 7.1 years. All patients were treated with 720,000 IU/kg of IL-2 administered by a 15-minute intravenous infusion every 8 hours for up to 5 days, as clinically tolerated per cycle. Patients were retreated according to clinical response and tolerance to the IL-2 therapy. Of the 149 patients with melanoma, 10 achieved complete responses (CRs) and 13 partial responses (PRs), for an overall response rate of 15.4%. Of the 201 patients with renal cell cancer, 18 achieved CRs and 20 PRs, for an overall response rate of 19.0%. Among responding patients, 21 of 23 with melanoma and 34 of 38 with renal cell cancer developed at least PRs after the first course of IL-2. Most patients with metastatic melanoma and renal cell cancer who achieved PRs or CRs to intravenous high-dose bolus IL-2 were identified after the first course of therapy. Those who demonstrated no response after two treatment courses failed to respond to additional IL-2 therapy. Based on this retrospective analysis, we recommend that patients who exhibit objective responses to treatment with high-dose bolus IL-2 receive additional treatment courses until either CR or IL-2 intolerance develops. Patients who do not achieve objective responses after two courses of IL-2 should receive no further treatment with this regimen.

Prospective sonographic evaluation of interleukin-2-induced changes in the gallbladder.

To describe the changes in the gallbladder induced by interleukin-2 (IL-2) therapy and to correlate the findings with the clinical course. Twenty-five men with human immunodeficiency virus (HIV) infection were examined prospectively with right upper quadrant ultrasonography (US) before and after receiving IL-2 therapy. Four patients also underwent US after a second course of IL-2. The gallbladder was evaluated for wall thickening, echotexture, and intramural and pericholecystic fluid. Correlation was made between the clinical signs and symptoms, IL-2 dose, CD4 cell count, and the US appearance of the gallbladder. There was significant correlation between symptoms of right upper quadrant pain during IL-2 therapy and US abnormalities of the gallbladder, including an increase in wall thickening (P = .012) and the development of intramural (P = .015) and pericholecystic (P = .006) fluid. More severe abnormalities were seen with higher IL-2 doses. All symptoms resolved with cessation of IL-2 therapy. In patients who underwent repeat US, the gallbladder reverted to a normal appearance. No correlation was found between the CD4 cell count and the development of symptoms or the US appearance of the gallbladder. IL-2-induced changes resolve rapidly with cessation of therapy, and no surgical intervention is needed. These changes can be avoided or reduced by decreasing the IL-2 dose during subsequent cycles.

NEPHRECTOMY BEFORE INTERLEUKIN-2 THERAPY FOR PATIENTS WITH METASTATIC RENAL CELL CARCINOMA

Purpose The management of metastatic renal cell carcinoma remains challenging and controversial. There is some evidence of improved response to interleukin-2 (IL-2) based immunotherapy in patients who undergo nephrectomy before systemic treatment. However, recent reports have suggested that surgery prior to immunotherapy may not be an efficient strategy, since many patients will not be able to receive systemic treatment after nephrectomy. We describe our criteria for determining which patients are candidates for nephrectomy before immunotherapy and present our series of patients treated with this approach. Materials and Methods Based on our initial experience with IL-2 based immunotherapy we developed certain inclusion criteria for treatment with initial nephrectomy followed by systemic immunotherapy, including greater than 75% debulking of tumor burden possible, no central nervous system, bone or liver metastases, adequate pulmonary and cardiac function, and Eastern Cooperative Oncology Group performance status of 0 or 1. In addition, patients in whom biopsies show other than predominantly clear cell type histology are excluded. From 1991 through 1996, 28 patients met these criteria and were treated with this approach. Patients were followed to determine the number receiving immunotherapy as well as overall response and survival rates. Results Radical nephrectomy was performed in all patients. One patient died of respiratory failure from disease progression 1 month after nephrectomy. Another patient had poor pulmonary function and, therefore, was treated with an alternative cytokine therapy. The remaining 26 patients (93%) received at least 1 course of IL-2. Median interval between nephrectomy and initiation of immunotherapy was 1.5 months (range 1 to 3). Overall response rate was 39% with 5 complete (18%) and 6 partial (21%) responses. Actuarial median survival of the entire group was 20.5 months (range 1 to 66) from the initiation of treatment. Currently 13 patients are alive, including 8 who are disease and/or progression-free. Conclusions Using these strict criteria nephrectomy can be effectively performed before immunotherapy without compromising the likelihood that patients will receive systemic treatment. The activity of IL-2 in patients treated with this approach is encouraging and justifies its consideration in properly selected patients.