Walter J. Urba

Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

BACKGROUND An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cell Carcinoma

PURPOSE The Cytokine Working Group conducted a randomized phase III trial to determine the value of outpatient interleukin-2 (IL-2) and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m(2) subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m(2) subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks. RESULTS One hundred ninety-two patients were enrolled between April 1997 and July 2000. Toxicities were as anticipated for these regimens. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (nine of 91 patients) for IL-2/IFN (P = .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and IFN (P = .082). The median response durations were 24 and 15 [corrected] months (P = .18) [corrected] and median survivals were 17.5 and 13 months (P = .24). For patients with bone or liver metastases (P = .001) or a primary tumor in place (P = .040), survival was superior with HD IL-2. CONCLUSION This randomized phase III trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic renal cell carcinoma.

Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: the low probability for cure.

PURPOSE The study was undertaken to evaluate clinical prognostic factors, probability of response to therapy, duration of response, and overall survival of patients with Hodgkins disease relapsing from a chemotherapy-induced complete remission. PATIENTS AND METHODS Study population comprised 107 patients with Hodgkins disease treated with combination chemotherapy at the National Cancer Institute who relapsed after achieving a complete remission. RESULTS Half of the relapses occurred within the first year of achieving complete remission; among patients in remission 5 years or longer, only 4% relapsed. The overall survival of the relapsed patients is projected to be 17% at 20 years, calculated from the date of relapse. Primary treatment regimen, presence of B symptoms, stage, sex, liver involvement, pleural involvement, marrow involvement, and histologic subtype did not affect the survival of relapsed patients. Only age at diagnosis (older or younger than 30 years) and length of initial remission (shorter or longer than 1 year) made a significant impact on survival. Patients whose initial remission was longer than 1 year had significantly higher complete response rates to salvage therapy, significantly more durable second remissions, and significantly longer survival than patients whose initial remission was shorter than 1 year. Survival beyond 11 years from relapse of patients with long initial remissions was 24%; for those with short initial remissions, 11% (P2 = .027). Despite the fact that with salvage therapy, patients with long initial remission had an 85% complete response rate to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) with a disease-free survival of 45% at 20 years, acute leukemia and other treatment-related complications combined to lower the survival rate of this more favorable subset. CONCLUSIONS These data with conventional-dose salvage therapy provide results for comparison with novel salvage approaches including myeloablative therapy with autologous marrow or peripheral-blood stem-cell support.

Engagement of the OX-40 Receptor In Vivo Enhances Antitumor Immunity

The OX-40 receptor (OX-40R), a member of the TNFR family, is primarily expressed on activated CD4+ T lymphocytes. Engagement of the OX-40R, with either OX-40 ligand (OX-40L) or an Ab agonist, delivers a strong costimulatory signal to effector T cells. OX-40R+ T cells isolated from inflammatory lesions in the CNS of animals with experimental autoimmune encephalomyelitis are the cells that respond to autoantigen (myelin basic protein) in vivo. We identified OX-40R+ T cells within primary tumors and tumor-invaded lymph nodes of patients with cancer and hypothesized that they are the tumor-Ag-specific T cells. Therefore, we investigated whether engagement of the OX-40R in vivo during tumor priming would enhance a tumor-specific T cell response. Injection of OX-40L:Ig or anti-OX-40R in vivo during tumor priming resulted in a significant improvement in the percentage of tumor-free survivors (20–55%) in four different murine tumors derived from four separate tissues. This anti-OX-40R effect was dose dependent and accentuated tumor-specific T cell memory. The data suggest that engagement of the OX-40R in vivo augments tumor-specific priming by stimulating/expanding the natural repertoire of the host’s tumor-specific CD4+ T cells. The identification of OX-40R+ T cells clustered around human tumor cells in vivo suggests that engagement of the OX-40R may be a practical approach for expanding tumor-reactive T cells and thereby a method to improve tumor immunotherapy in patients with cancer.

Exacerbation of symptoms of autoimmune disease in patients receiving alpha-interferon therapy

The occurrence of autoimmune disease in patients receiving alpha‐interferon (α:‐IFN) therapy has been reported in several studies; these include autoimmune thyroiditis, thrombocytopenia, anemia, exacerbation of psoriasis, and the occurrence of sarcoidosis. The primary mechanism presumably is the emergence of autoantibodies to various structural proteins or receptors. Two studies have recently shown that a significant percentage of patients treated with recombinant alpha‐interferon (r α‐IFN) do form autoantibodies. The authors report six additional cases of development or exacerbation of autoimmune phenomena in patients receiving α‐IFN therapy. Five of these patients developed symmetric polyarthropathies and the sixth had thyroiditis. The presence of a history of underlying autoimmune disease or baseline serologic abnormalities in five of these patients, including the patient who developed thyroiditis, suggests that α‐IFN treatment can lead to the exacerbation of an underlying subclinical autoimmune process.

Adjuvant High-Dose Bolus Interleukin-2 for Patients With High-Risk Renal Cell Carcinoma: A Cytokine Working Group Randomized Trial

PURPOSE This prospective, randomized, controlled phase III trial assessed high-dose bolus interleukin-2 (IL-2) postoperatively in patients with high-risk renal cell carcinoma (RCC). PATIENTS AND METHODS Eligibility requirements were resected locally advanced (LA; T3b-4 or N1-3) or metastatic (M1) RCC, no prior systemic therapy, and excellent organ function. Randomized assignment was to one course of IL-2 (600,000 U/kg every 8 hours on days 1 to 5 and days 15 to 19 [maximum 28 doses]) or observation. The study was designed and powered to show an improvement in predicted 2-year disease-free survival (DFS) from 40% for the observation group to 70% for the treatment group. The accrual goal was 68 patients with LA disease, with 34 patients per treatment arm. Metastasectomy patients were to be analyzed separately because of their unpredictable natural history. RESULTS Sixty-nine patients were enrolled onto the study (44 LA and 25 M1 patients). Toxic effects of IL-2 were as anticipated; no unexpected serious adverse events or treatment-related deaths occurred. Early closure occurred when an interim analysis determined that the 30% improvement in 2-year DFS could not be achieved despite full accrual. Sixteen of 21 LA patients receiving IL-2 experienced relapse, compared with 15 of 23 patients in the observation arm (P =.73); in the LA group, three deaths occurred in the IL-2 arm, and five deaths occurred in the observation arm (P =.38). Analysis including metastasectomy patients made no difference in DFS or overall survival. CONCLUSION One course of high-dose bolus IL-2, though feasible, did not produce the ambitious clinically meaningful benefit anticipated when administered postoperatively to patients with resected high-risk RCC.

Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies.

Cancer immunotherapy centers on modulating the hosts tumor‐directed immune response. One promising approach involves augmentation of cell‐mediated immunity by interrupting T‐cell pathways responsible for immune down‐regulation or tolerance. The discovery of cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) and its role as a key negative regulator for T cells has prompted efforts to target this signaling molecule to improve cancer therapy. Activation, or ‘priming’, of naive T cells in response to tumor‐cell invasion comprises a dual‐signaling mechanism. Signal 1 requires tumor‐associated antigen recognition by the T‐cell receptor, while signal 2 occurs through binding of CD80 or CD86 (B7.1 of 2) on the antigen presenting cell (APC) with CD28 on the T cell. Importantly, there is a final step responsible for naturally occurring immune regulation; this occurs in response to competitive binding of CD80/CD86 on the APC by CTLA‐4 on the T cell. This ‘immune checkpoint’ interrupts signal 2 and inhibits the activated T cell. Targeting CTLA‐4 as an anticancer strategy: Following proof‐of‐concept studies in animals, fully human anti‐CTLA‐4 antibodies were developed and 2 are undergoing clinical evaluation. Ipilimumab and tremelimumab have shown promising antitumor activity, initially in patients with advanced melanoma. Class‐specific immune‐related adverse events (irAEs) were common and mostly transient and/or manageable. These events are thought to be mechanism‐of‐action‐related, indicating immune tolerance is broken; this relation may also explain the association between irAEs and response seen in several trials. Interruption of immune inhibitory pathways via CTLA‐4 blockade appears to be a promising strategy for cancer immunotherapy. Cancer 2007.

OX40 Is a Potent Immune-Stimulating Target in Late-Stage Cancer Patients

OX40 is a potent costimulatory receptor that can potentiate T-cell receptor signaling on the surface of T lymphocytes, leading to their activation by a specifically recognized antigen. In particular, OX40 engagement by ligands present on dendritic cells dramatically increases the proliferation, effector function, and survival of T cells. Preclinical studies have shown that OX40 agonists increase antitumor immunity and improve tumor-free survival. In this study, we performed a phase I clinical trial using a mouse monoclonal antibody (mAb) that agonizes human OX40 signaling in patients with advanced cancer. Patients treated with one course of the anti-OX40 mAb showed an acceptable toxicity profile and regression of at least one metastatic lesion in 12 of 30 patients. Mechanistically, this treatment increased T and B cell responses to reporter antigen immunizations, led to preferential upregulation of OX40 on CD4(+) FoxP3(+) regulatory T cells in tumor-infiltrating lymphocytes, and increased the antitumor reactivity of T and B cells in patients with melanoma. Our findings clinically validate OX40 as a potent immune-stimulating target for treatment in patients with cancer, providing a generalizable tool to favorably influence the antitumor properties of circulating T cells, B cells, and intratumoral regulatory T cells.

Efficient Cross-presentation Depends on Autophagy in Tumor Cells

Cross-presentation of antigens is critical for the induction of adaptive immunity against tumor cells and infectious pathogens. Currently, it is not known how cross-presentation of tumor antigens is regulated by autophagy. Using both HEK 293T cells that expressed the model antigen OVA and melanoma cells as antigen donors, we show that macroautophagy in tumor cells is essential for cross-presentation by dendritic cells both in vitro and in vivo. Inhibition of autophagy abolished cross-presentation almost completely, whereas induction of autophagy dramatically enhanced the cross-presentation of tumor antigens. Moreover, purified autophagosomes were found to be efficient antigen carriers for cross-presentation. Our findings not only identified a novel role for autophagy as an active process in antigen sequestration and delivery to dendritic cells for cross-presentation, but also suggested, for the first time, that isolated autophagosomes may have potential as potent vaccines for immunotherapy against cancer and infectious diseases.

Resistance to Recombinant Interferon Alfa-2a in Hairy-Cell Leukemia Associated with Neutralizing Anti-Interferon Antibodies

To explain the hematologic deterioration occasionally observed during interferon therapy, we assayed serum specimens from 51 patients with hairy-cell leukemia receiving treatment with recombinant interferon alfa-2a for the presence of anti-interferon antibodies. After a median of seven months of therapy, anti-interferon antibodies were found in 31 patients. Fifteen of these patients had only non-neutralizing antibodies, but antibody from the other 16 neutralized the antiviral effects of recombinant interferon alfa-2a in vitro. In no case, however, did neutralizing antibody inhibit the antiviral effects of purified natural interferon alfa. Clinical resistance to interferon of various degrees was present in 6 of 16 patients with neutralizing antibodies; the remaining 10 patients and all 20 patients without antibody continue to respond after a minimum of two years of therapy. In all the patients with interferon resistance, antibody was present when it developed. These data suggest that the development of clinical resistance to interferon alfa-2a in hairy-cell leukemia is not necessarily related to an altered cellular response to interferon. Treatment with other interferons, such as purified natural interferon alfa, may be useful in patients with clinically important neutralizing antibodies against interferon alfa-2a.