Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study.

BACKGROUND: This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy. PATIENTS AND METHODS: In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response. RESULTS: Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3-13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8-6.1 months). CONCLUSIONS: In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/kg ± radiotherapy are ongoing. ClinicalTrials.gov identifier: NCT00323882.

A phase I/IIA study of AGS-PSCA for castration-resistant prostate cancer.

BACKGROUND: This first-in-human phase I/IIA study was designed to evaluate the safety and pharmacokinetics (PKs) of AGS-PSCA a fully human monoclonal antibody directed to prostate stem cell antigen (PSCA) in progressive castration-resistant prostate cancer. PATIENTS AND METHODS: Twenty-nine patients were administered infusions of AGS-PSCA (1-40 mg/kg) every 3 weeks for 12 weeks; 18 final patients received a 40-mg/kg loading dose followed by 20-mg/kg repeat doses. Primary end points were safety and PK. Immunogenicity, antitumor activity and circulating tumor cells were also evaluated. RESULTS: No drug-related serious adverse events were noted. Dose escalation stopped before reaching the maximum tolerated dose as target concentrations were achieved. Drug levels accumulated linearly with dose and the mean terminal half-life was 2-3 weeks across dose levels. The 40-mg/kg loading dose followed by repeated 20-mg/kg doses yielded serum drug concentrations above the projected minimum therapeutic threshold after two to three doses without excessive drug accumulation or toxicity. Significant antitumor effects were not seen. CONCLUSIONS: A 40-mg/kg loading dose followed by 20-mg/kg infusions every 3 weeks is the recommended phase II dose of AGS-PSCA. PSCA is a promising drug target and studies in prostate and other relevant solid tumors are planned.

An electrodiagnostic evaluation of the effect of pre-existing peripheral nervous system disorders in patients treated with the novel proteasome inhibitor bortezomib.

AIMS: Bortezomib (Velcade), a novel proteasome inhibitor, has shown promise in the treatment of malignancies, including multiple myeloma and non-Hodgkin's lymphoma. Several studies have identified neuropathy as a potentially dose-limiting side effect of treatment with bortezomib. We report the clinical and electrodiagnostic data from four patients who developed signs and symptoms of peripheral neuropathy from treatment with bortezomib. MATERIALS AND METHODS: Patients were included if they were enrolled in active phase 2 trials of bortezomib for non-Hodgkin's lymphoma or prostate cancer, developed signs and symptoms of peripheral neuropathy, and were referred for electrodiagnostic evaluation. RESULTS: Four patients, including two with non-Hodgkin's lymphoma and two with prostate cancer, underwent electrodiagnostic testing. Electrodiagnostic evaluation showed pre-existing peripheral nervous system disorders in three out of four patients. Multiple peripheral nervous system disorders were present in two out of four patients. CONCLUSIONS: Bortezomib can cause a predominately sensory axonal polyneuropathy. Pre-existing peripheral nervous system disorders, such as neuropathy and radiculopathy, are common in patients with cancer, and may pre-dispose to the development of symptomatic neuronal toxicity when treated with bortezomib. Baseline electrodiagnostic evaluation may identify patients with pre-existing peripheral nervous system disorders at risk for additive neuronal toxicity from neurotoxic chemotherapeutic agents.

Elution of tumor-directed antibody from kidneys of mammary tumor-bearing mice.

Immunoglobulin-containing eluates, prepared from kidneys of Paris RIII mammary tumor-bearing mice approximately 10 months old, were incubated with frozen sections of mouse mammary tumor and normal lactating mammary gland and examined by immunofluorescence. The eluates diffusely strained the tumor but did not stain the nonneoplastic lactating mammary gland. Mammary tumor and normal lactating mammary gland were both stained by an antiserum to mammary tumor virus (MuMTV). The euglobulin portion of the eluates, when fractionated on a Sephadex G-200 column, yielded an IgG fraction which was shown by immunodiffusion to react with Paris RIII mammary tumor extract and with anti-mouse globulin but not with nonneoplastic mouse tissue extracts. Since the lactating mammary glands of these animals contain MuMTV, the antibody-containing fraction eluted from the kidneys appeared to be tumor directed rather than virus directed.

Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer.

PURPOSE: To determine the safety and activity of weekly paclitaxel in combination with estramustine and carboplatin (TEC) in patients with advanced prostate cancer. PATIENTS AND METHODS: In a dose-escalation study, patients with advanced prostate cancer were administered paclitaxel (weekly 1-hour infusions of 60 to 100 mg/m(2)), oral estramustine (10 mg/kg), and carboplatin (area under the curve, 6 mg/mL-min every 4 weeks). Paclitaxel levels were determined 0, 30, 60, 90, and 120 minutes and 18 hours after infusion, and a concentration-time curve was estimated. Once a safe dose was established, a multi-institutional phase II trial was conducted in patients with progressive androgen-independent disease. RESULTS: Fifty-six patients with progressive androgen-independent disease were treated for a median of four cycles. The dose of paclitaxel was escalated from 60 to 100 mg/m(2) without the occurrence of DLT. Posttherapy decreases in serum prostate-specific antigen levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% (95% confidence interval, 55% to 79%, 35% to 61%, 26% to 52%) of the patients, respectively. Of the 33 patients with measurable disease, two (6%) had a complete response and 13 (39%) had a partial response. The overall median time to progression was 21 weeks, and the median survival time for all patients was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic disease (in 25% of patients), hyperglycemia (in 38%), and hypophosphatemia (in 42%). Significant leukopenia, thrombocytopenia, and peripheral neuropathy were not observed. CONCLUSION: TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer.

Expression of potential target antigens for immunotherapy on primary and metastatic prostate cancers.

Defining the expression of tumor-associated antigens on primary and metastatic prostate cancer is the crucial first step in selecting appropriate targets for immune attack. In this study, the distribution of the tumor-associated antigens GM2, Tn, sTn, Thompson-Friedenreich antigen (TF), Globo H, Le(y), MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC7, carcinoembryonic antigen, beta chain of human chorionic gonadotropin (hCG beta), HER2/neu, PSMA, and KSA on primary and metastatic prostate cancer and 16 types of normal tissues was compared by immunohistochemistry, using a panel of well-characterized monoclonal antibodies. Our results show that GM2, KSA, and MUC2 were strongly expressed on 8 or 9 of 9 metastatic prostate cancer biopsy specimens and, with PSMA, hCG beta, TF, Tn, and sTn, on 8 or more of 11 primary prostate cancer specimens. Tn, MUC1, and PSMA were expressed on 4-6 of 9 metastatic specimens. The remaining antigens were expressed on no more than three of nine metastatic specimens. Normal tissues were also tested with all antibodies. With regard to the eight antigens most widely expressed on prostate cancers, PSMA was not expressed significantly on any of the normal tissues except prostate epithelium. Tn, sTn, hCG beta, and MUC2 were detected on up to 3 of 10 types of normal epithelia. GM2, TF, MUC1, and KSA were more broadly distributed on normal epithelia, all primarily at the secretory borders. STn, KSA, and hCG beta were also detected in the testis, and GM2 was expressed on gray matter of brain. From the 30 antigens that we have screened, this study provides the basis for selecting GM2, TF, Tn, sTn, hCG beta, MUC1, MUC2, KSA, and PSMA as target antigens for specific immunotherapy of prostate cancer.

Interferon-gamma and monoclonal antibody 131I-labeled CC49: outcomes in patients with androgen-independent prostate cancer.

To assess the tumor targeting, safety, and efficacy of monoclonal antibody 131I-labeled CC49 in patients with androgen-independent prostate cancer, 16 patients received 75 mCi/m2 of the radiolabeled antibody after 7 days of IFN-gamma pretreatment. Sequential tumor biopsies in three patients showed a median 5-fold (range, 2-6-fold) increase in the proportion of cells staining positively for the TAG-72 antigen, whereas one showed a decrease in staining. Fourteen patients received 131I-labeled CC49, whereas 2 showed a disease-related decrease in performance status, precluding antibody treatment. The antibody localized to sites of metastatic androgen-independent prostate cancer in 86% (12 of 14; 95% confidence interval, 57-95%) of cases. Both osseous and extraosseous sites were visualized, and in six (42%) patients, more areas were visible when the radioimmunoconjugate was used than were apparent when conventional scanning techniques were used. The localization of the conjugate in the marrow cavity was usually a site not visualized by the radionuclide bone scan, in which the isotope localizes primarily to the tumor-bone interface. The dose-limiting toxicity was thrombocytopenia because five (36%) patients showed grade IV and seven (50%) showed grade III effects. In addition, six (42%) patients, four of whom were hospitalized, showed a flare in baseline pain, and four showed a decrease in pain. No patient showed a >50% decline in prostate-specific antigen, although radionuclide bone scans remained stable in four cases for a median of 4 months. The results are consistent with dosimetry estimates showing that the delivered dose to tumor was subtherapeutic and suggest that approaches that exclusively target the bone tumor interface or the marrow stroma may be unable to completely eradicate disease in the marrow cavity. For CC49, improving outcomes would require repetitive dosing, which was precluded by the rapid development of a human antimouse antibody response.

Immunotherapeutic approaches to the treatment of bone and soft tissue sarcomas.

The recent explosion of knowledge in the field of immunology has resulted in the development of many new and exciting forms of treatment for cancer patients. The identification of murine MoAbs with reactivity against antigens found on sarcomas has been accomplished in recent years. However, many problems exist with these reagents. As these antibodies are raised in mice, they represent foreign proteins for humans. As such, the development of immunity against the antibodies has been one of the major problems in applying this modality in the clinic. Other problems, such as specificity, antigenic modulation, tumor cell heterogeneity, and trafficking of the antibody to the tumor, remain to be resolved. Current research involving the development of chimeric or human MoAbs may overcome some of these obstacles. Cell-mediated approaches to therapy have met with enthusiasm and modest success so far. Although LAK cell therapy has not resulted in tumor regressions in the small number of sarcoma patients treated, further studies to define the true response rate are underway. It is possible that treatment with tumor-specific cells such as TIL or "educated" lymphocytes will be more effective in attaining regression in patients with metastatic bone and soft tissue sarcomas.

Peptide and carbohydrate vaccines in relapsed prostate cancer: immunogenicity of synthetic vaccines in man--clinical trials at Memorial Sloan-Kettering Cancer Center.

Men with rising prostate-specific antigen (PSA) levels after primary therapies such as prostatectomy or radiotherapy represent a unique group for whom no standard treatment option exists. A variety of approaches including expectant monitoring, dietary modification, hormonal therapy, and alternative medicines have shown an impact on the rate of increase in PSA, but the overall effect on survival remains controversial. At Memorial Sloan-Kettering Cancer Center, we have focused our treatment approach on this cohort of patients in a series of phase I monovalent carbohydrate and glycoprotein-conjugate vaccine trials using the patients' immune system to generate an antitumor response. These synthetic vaccines are conjugated to keyhole limpet hemocyanin (KLH) and given with the immunologic adjuvant QS21 as five subcutaneous vaccines over 26 weeks. All patients generated specific high-titer immunoglobulin M (IgM) and/or IgG antibodies, some of which were able to mediate complement lysis. Preliminary data suggest that these vaccines may impact on the rate of increase in posttreatment PSA slopes compared with pre-PSA values. The impact of vaccine therapy on the PSA slope and its effect on the time to radiographic progression are the current focus of a forthcoming phase II trial. Vaccines may offer an alternative treatment option for the patient who has relapsed early following primary therapies.

Clinical use of posttherapy prostate-specific antigen changes in advanced prostate cancer.

Posttherapy changes in prostate-specific antigen (PSA) have been used as a primary endpoint for patients with prostate cancer in an effort to rapidly identify promising therapeutic approaches. Using this method, agents that do not produce a defined decline in PSA on multiple determinations for a specified period are not to be pursued further. Multiple investigators have used PSA as an outcome measure, but the results are variable and often difficult to interpret. These inconsistencies are due to the lack of a consensus on criteria for PSA declines and the inappropriate use of PSA as an and point when it is not clinically applicable. Phase III studies are needed to validate any surrogate variable, including posttherapy declines in PSA; until such trials have been performed, investigators need to define and report all parameters of outcome independently.

Targeted therapy for prostate cancer: the Memorial Sloan-Kettering Cancer Center approach.

Carcinoma of the prostate represents a wide range of diseases with differing prognoses. A key to selecting treatment depends on the ability to predict the natural history of the disease for the individual. Thus far, non-hormonal approaches have not demonstrated a survival advantage in randomized comparisons and, clearly, innovative approaches are needed. The clinical trials program developed at Memorial Sloan-Kettering Cancer Center is based on specific manifestations and specific targets of the disease and the predicted prognosis, using prostate-specific antigen and acid phosphatase changes as biomarkers of progression and response. In patients with minimal disease who have received local treatments but progressed systemically, we are studying methods aimed at stimulating their immune systems either by nonspecific immunopotentiation or specific immunization to specific glycoprotein or carbohydrate targets on the cancer cells, or to anti-growth factor receptor antibody aimed at blocking the specific signalling pathways that contribute to hormonal failure. These and other approaches provide an opportunity to treat this disease while maintaining an acceptable quality of life for patients.

Tumor directed antibody and carcinoembryonic antigen in the glomeruli of a patient with gastric carcinoma.

A patient dying of gastric carcinoma was one of a group of cancer patients examined for the presence of glomerular immune complex deposits not associated with the nephrotic syndrome. The deposits were distributed in the mesangial and subendothelial regions. This distribution is found in experimental animals with neoplasia and glomerulopathy as well as in over 30 per cent of humans with cancer. Immunofluorescence showed IgG and C3 in the patient's glomeruli. Carcinoembryonic antigen was identified in the patient's glomeruli by the immunoperoxidase staining method. An IgG antibody was eluted from the kidney and found to be reactive with the patient's tumor, as well as another patient's colonic carcinoma. This reactivity was blocked by preincubation of the tumor substrate with anticarcinoembryonic antigen. Thus, both a tumor associated antigen and a corresponding antibody were shown to be contained in the glomerular deposits. It is concluded that circulating immune complexes of high molecular weight containing carcinoembryonic antigen produced by the gastric carcinoma led to the formation of subendothelial deposits without significant renal damage. This is in contrast to the usual finding of membranous glomerulonephritis among cancer patient with the nephrotic syndrome and more closely resembles the animal models. Whereas tumor reactive antibodies can be found in the glomeruli of patients with cancer, a specific tumor associated antigen to which the antibody is reactive has only occasionally been demonstrated.

Vaccines as treatment strategies for relapsed prostate cancer: approaches for induction of immunity.

Prostate cancer is a important tumor in which to evaluate vaccine strategies. It is associated with two well-characterized serum biomarkers, prostate specific antigen (PSA) and prostatic acid phosphatase, which enables the investigator to monitor the progress of the disease. There are well-studied but less well-known glycoprotein and glycolipid antigens on the surface of prostate cancer cells that may function as targets for immune recognition and attack. Conventional treatments such as chemical castration are often poorly tolerated. When initiation of hormonal therapy is controversial, alternative therapies with minimal side effects are a desirable approach. Vaccines represent a means by which the immune system can be stimulated in order to affect an antitumor response by means of recruiting a variety of different effector arms of the immune system. The varying approaches toward vaccine construction as treatment strategies for relapsed prostate cancer are described.

Steroid hormone withdrawal syndromes. Pathophysiology and clinical significance.

The steroid withdrawal syndrome has brought a new dimension to the treatment of advanced prostate cancer not only in the way we treat androgen-independent disease but also in terms of insights into the development of hormonal resistance. The data now confirm that 30% of cases have a meaningful subjective, biochemical, and objective response to the withdrawal of a steroid hormone as the first maneuver after primary hormonal therapy failure. Larger studies are needed to define further the withdrawal effect related to the other steroid hormone family members and to determine the objective response proportions. Although controversy surrounds the cause of the steroid withdrawal phenomenon, studies suggest that the androgen receptor plays a pivotal role. Molecular studies of the androgen receptors involving larger number of patients are paramount if we are going to develop a better understanding of the evolution of the withdrawal effect and hormone resistance.

Chemotherapy for androgen- independent prostate cancer: myth or reality.

In the past, the treatment options for patients with metastatic prostate cancer that progressed despite castrate levels of testosterone was limited, and no therapies provided an improvement in survival. The majority of these patients had extensive osseous disease, multiple comorbidities, and poor performance status. With the widespread use of prostate-specific antigen (PSA) to monitor their clinical course, patients have presented with less extensive disease and a better performance status. Clinical trial methodology has improved as well, through incorporation of post-therapy changes in PSA to evaluate novel agents. This approach allows more patients to enter clinical trials, and the results show that the majority of these patients will have significant reduction in pain, regression of measurable disease, and suppression of PSA. These data suggest that prostate cancer is not as resistant to chemotherapy as it was once thought to be.

Rising PSAs after primary therapy: active or passive intervention.

Prostate cancer that has relapsed biochemically after primary therapies, such as prostatectomy or radiation, remains a therapeutic challenge in that no standard treatment option exists for this patient. These patients are often young and may be offered androgen ablation as the mainstay of treatment. Many patients do not wish to undergo a regimen that may be associated with a variety of side effects that will impact on their quality of life. Delaying hormonal treatment in this group does not compromise survival and patients may try a variety of approaches in an attempt to control rising PSAs. Therefore, these patients are an interesting subgroup for whom immunological and alternative therapies may prove to be beneficial. We review new approaches for this population of men, which result in antitumor effects with minimal toxicities.

Epstein--Barr virus nuclear antigen in a non-Hodgkin's lymphoma.

This paper describes the course of a patient with treated non-Hodgkin's lymphoma, which originally presented as a large nasopharyngeal mass. The tumor, though irradiated, recurred on two separate occasions in the right and left inguinal regions. At the time of tumor recurrence, markers were present which have been associated with past or recurrent Epstein-Barr virus (EBV) infection, namely, antibodies to the EBV viral capsid antigen (VCA) and the Epstein-Barr nuclear antigen (EBNA). EBNA was detected in approximately 10% of the neoplastic cells. An unusual immunoglobulin heavy and light chain switch within the tumor cells of the two separate inguinal node tumor recurrences was also observed. Whether EBV plays a role in the pathogenesis of lymphomas remains unclear.

Harnessing T-lymphocytes for human cancer immunotherapy.

After nearly a decade of controversy, the concept of adoptive immunotherapy in humans is gaining greater acceptance. More recently, investigators have made use immunotherapeutically of T-lymphocytes nonspecifically activated in vitro by a number of agents, including lymphokines, lectins, and autologous and allogeneic tumor cells. The limitations for the investigational use of these highly specialized and "educated" lymphocytes have been the inability to generate sufficient numbers of cells in vitro for adoptive transfer experiments and to sustain their growth over long periods of time. While marked success has been demonstrated over the years in tumor-bearing animal models, the feasibility of such work in humans has been greatly improved by the experimental expansion and maintenance of immune lymphocytes (those exposed to antigenic challenge) in vitro using either highly purified or recombinant, interleukin 2. As a result, large numbers of lymphocytes can successfully be infused into patients, and whole body scans can show migration of these labeled cells to the lung, liver, and spleen. The use of nontoxic, nonspecific activated "killer" lymphocytes is an innovative approach with enormous potential. This report presents discussion of these findings and addresses the issue of an alternative approach to cancer treatment therapy, the in vivo use of cloned cytotoxic T-lymphocytes sensitized to the autologous tumor.