Use Of Antibody Therapy Research Articles

Fostering collaborative care in multiple myeloma: The impact of holistic education on decision-making with antibody and CAR-T platforms.

e21008 Background: The management of multiple myeloma (MM) continues to be transformed by evidence supporting the use of CD38 antibodies and B-cell maturation antigen (BCMA) immunotherapy (chimeric antigen receptor (CAR-T) and bispecific antibodies) in newly diagnosed and relapsed/refractory MM (NDMM and RRMM), respectively. However, real-world evidence and survey data show that these approaches are under-utilized across lines of therapy and that educational outreach to patients on their use is inadequate (Puig N et al. ASH 2022. Abstract 1859; Pink S et al. ISPOR 2022. Abstract HSD44; Terpos E et al. Blood Cancer J. 2021;11:40; Adu Y et al. ASH 2023. Abstract 2418). Methods: To address these gaps, PeerView partnered with HealthTree Foundation for Multiple Myeloma to develop 4 live events and 5 online enduring activities from 06/2022 to 06/2023, to educate clinicians on the evidence and principles for integrating CD38 and BCMA antibody platforms into patient care. The activities’ core objectives focused on improving knowledge and skills for integrating CD38 antibodies and BCMA immunotherapy platforms into sequential MM treatment. Furthermore, through the partnership with HealthTree Foundation, the initiatives featured patient perspectives as well as tools and resources to foster clinician–patient communication on use of antibody and CAR-T therapy. Pre- and post-activity multiple choice questions measured changes in knowledge and skills. Responses from enduring activity learners were compared with those from a matched sample of nonparticipants. In a meta-analysis of outcomes from the 9 activities, learning objectives were grouped by key themes, with changes in knowledge and skills averaged across them. Results: Total learners: 12,248 (hematologist-oncologists/oncologists: 7,345; oncology nurses: 1,247) In all activities, learners’ knowledge and skills improved, with increases of: 35 percentage points (ppt) in knowledge of new evidence and changing practice guidelines supporting BCMA antibody platforms in RRMM (44% to 79%); 36 ppt in skills in treatment planning and evidence-based integration of CD38 and BCMA-targeting antibodies in the management of MM (52% to 88%); 46 ppt in ability to address safety considerations related to the use of antibody therapy and BCMA immunotherapy (39% to 85%); 58 ppt in patient interaction skills (eg, counseling, shared decision-making) when using antibody-based and CAR-T platforms (28% to 86%). Conclusions: Improvements in knowledge and skills, combined with a greater focus on patient-centricity, suggest that learners are poised to more effectively integrate CD38 antibodies and BCMA immunotherapy into guideline-recommended MM care that improves the overall well-being and outcomes of patients with MM.

Induction Therapy and Therapeutic Antibodies.

Prevention of allograft rejection is one of the crucial goals in solid organ transplantation to ensure durability of the graft and is chiefly mediated by cellular and humoral pathways targeting cell surface alloantigens. The risk of rejection is highest in the first post-transplant year and wanes with time albeit the risk always exists and varies with the type of organ transplanted. Induction therapies refer to the use of high-intensity immunosuppression in the immediate post-operative period to mitigate the highest risk of rejection. This term encompasses chiefly the use of antibody therapies directed against one of the key pathways in T-cell activation or abrogating effects of circulating alloantibodies. These antibodies carry more potent immunomodulatory effect than maintenance immunosuppressive therapy alone and many of them lead to durable immune cell depletion. A variety of monoclonal and polyclonal antibodies have been utilized for use not only for induction therapy, but also for treatment of allograft rejection when it occurs and as components of desensitization therapy before and after transplantation to modulate circulating alloantibodies.

Perinatal Inflammation: Could Partial Blocking of Cell Adhesion Molecule Function Be a Solution?

In spite of the great advances made in recent years in prenatal and perinatal medicine, inflammation can still frequently result in injury to vital organs and often constitutes a major cause of morbidity. It is today well established that in neonates—though vulnerability to infection among neonates is triggered by functional impairments in leukocyte adhesion—the decreased expression of cell adhesion molecules also decreases the inflammatory response. It is also clear that the cell adhesion molecules, namely, the integrins, selectins, and the immunoglobulin (Ig) gene super family, all play a crucial role in the inflammatory cascade. Thus, by consolidating our knowledge concerning the actions of these vital cell adhesion molecules during the prenatal period as well as regarding the genetic deficiencies of these molecules, notably leukocyte adhesion deficiency (LAD) I, II, and III, which can provoke severe clinical symptoms throughout the first year of life, it is anticipated that intervention involving blocking the function of cell adhesion molecules in neonatal leukocytes has the potential to constitute an effective therapeutic approach for inflammation. A promising perspective is the potential use of antibody therapy in preterm and term infants with perinatal inflammation and infection focusing on cases in which LAD is involved, while a further important scientific advance related to this issue could be the combination of small peptides aimed at the inhibition of cellular adhesion.

The Principles of Antibody Therapy for Infectious Diseases with Relevance for COVID-19.

Antibody therapies such as convalescent plasma and monoclonal antibodies have emerged as major potential therapeutics for coronavirus disease 2019 (COVID-19). Immunoglobulins differ from conventional antimicrobial agents in that they mediate direct and indirect antimicrobial effects that work in concert with other components of the immune system. The field of infectious diseases pioneered antibody therapies in the first half of the 20th century but largely abandoned them with the arrival of conventional antimicrobial therapy. Consequently, much of the knowledge gained from the historical development and use of immunoglobulins such as serum and convalescent antibody therapies was forgotten; principles and practice governing their use were not taught to new generations of medical practitioners, and further development of this modality stalled. This became apparent during the COVID-19 pandemic in the spring of 2020 when convalescent plasma was initially deployed as salvage therapy in patients with severe disease. In retrospect, this was a stage of disease when it was less likely to be effective. Lessons of the past tell us that antibody therapy is most likely to be effective when used early in respiratory diseases. This article puts forth three principles of antibody therapy, namely, specificity, temporal, and quantitative principles, connoting that antibody efficacy requires the administration of specific antibody, given early in course of disease in sufficient amount. These principles are traced to the history of serum therapy for infectious diseases. The application of the specificity, temporal, and quantitative principles to COVID-19 is discussed in the context of current use of antibody therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Abstract 1746: Epigenetic modulation of the tumor microenvironment enhances immune checkpoint efficacy in a murine model of pancreatic cancer

Abstract This project aims to test the hypothesis that the epigenetic modulatory drug (EMD), entinostat, is capable of altering the inflammatory environment of pancreatic ductal adenocarcinoma (PDAC) and sensitizing it to checkpoint blockade inhibition. Recently the use of antibody therapy targeting immune checkpoints, such as CTLA-4 and PD-1, has become a major focus of cancer immunotherapy. In responsive patients, these therapies have resulted in long-term control of chemotherapy-resistant disease. The most compelling activity has been seen in the minority of patients with immunogenic tumors where T cell infiltration naturally occurs. These benefits are not observed in nonimmunogenic tumors, such as PDAC, with low expression of tumor-associated antigens (TAA) and a lack of intrinsic T cell infiltrate. Therapies that can alter the tumor microenvironment (TME) and allow infiltration of effector T cells, decrease of immunosuppressive cells, and stimulate TAA expression may convert nonimmunogenic tumors into cancers sensitive to checkpoint inhibitors. Recent work with EMDs has shown that they are capable of altering the immunogenicity of the TME by inducing the expression of cancer testis antigens as well as increasing tumor cell expression of MHC class II. We aim to test the hypothesis that treatment with EMDs can sensitize the inflammatory environment of PDAC to checkpoint blockade inhibition by evaluating changes of immune cells within the TME via flow cytometry, immunohistochemistry, and gene expression array. We are using a murine model of hepatic metastases of pancreatic cancer, which involves injecting syngeneic pancreatic tumor cells into the spleen followed by a hemisplenectomy, resulting in the consistent formation of hepatic metastases. We have evaluated entinostat, a histone deacetylase inhibitor, in combination with anti-PD-1 and demonstrated a significant survival benefit compared to either agent alone. Flow cytometric analysis of the TME shows that the combination of entinostat and anti-PD-1 causes a significant shift from an M-MDSC dominated to a more G-MDSC population. Additionally, the M-MDSC population expressed less arginase-1 while the G-MDSC population expressed less PD-L1, indicating inhibited immunosuppressive function. By adding anti-CTLA-4 to entinostat and anti-PD-1 combination therapy, the infiltration of granzyme-B-producing CD8+ T effector cells is significantly increased, correlating with improved survival. Current studies aim to further elucidate the functionality of the MDSC populations by isolating them to perform ex vivo immunosuppression assays as well as colorimetric arginase activity assays. Additionally, future studies aim to identify changes in gene expression profiles of isolated MDSC populations as well as general immune populations using the Nanostring platform. Citation Format: Brian Christmas, Blake Scott, Todd Armstrong, Nilofer Azad, Elizabeth Jaffee. Epigenetic modulation of the tumor microenvironment enhances immune checkpoint efficacy in a murine model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1746.

Entinostat in combination with nivolumab for patients with advanced cholangiocarcinoma and pancreatic adenocarcinoma.

TPS4151Background: The use of antibody therapy targeting immune checkpoints has become a major focus of cancer immunotherapy, with the most compelling activity seen in the minority of patients with...

Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients.

Registry data shows that between 15-35% kidney recipients will undergo treatment for at least one episode of acute rejection within the first post transplant year. Treatment options include pulsed steroid therapy, the use of an antibody preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the US, 61.4% patients with an acute rejection episode received steroids, 20.4% received an antibody preparation and 18.2% received both.To determine the benefits and harms of mono- or polyclonal antibodies (Ab) used to treat acute rejection in kidney transplant recipients.We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library, issue 2, 2005), MEDLINE (1966-June 2005), EMBASE (1980-June 2005), and the specialised register of the Cochrane Renal Group (June 2005).Randomised controlled trials (RCTs) in all languages comparing all mono- and polyclonal antibody preparations, given in combination with any other immunosuppressive agents, for the treatment of acute graft rejection, when compared to any other treatment for acute rejection.Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as relative risk (RR) with 95% confidence intervals (CI).Twenty one trials (49 reports, 1387 patients) were identified. Trials were generally small, incompletely reported, especially for potential harms, and did not define outcome measures adequately. Fourteen trials (965 patients) compared therapies for first rejection episodes. Ab was better than steroid in reversing rejection (RR 0.57, 95% CI 0.38 to 0.87) and preventing graft loss (death censored RR 0.74, CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection or death at one year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection. There was no benefit of muromonab-CD3 over ATG or ALG in either reversing rejection, preventing subsequent rejection, preventing graft loss or death.In reversing first rejection, any antibody is better than steroid and also prevents graft loss, but subsequent rejection and patient survival are not significantly different. In reversing steroid-resistant rejection the effects of different antibodies are also not significantly different. Given the clinical problem caused by acute rejection, data are very sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed.

Abstract 1686: Epigenetic modulation of the tumor microenvironment enhances vaccine induced T cell responses in a murine model of pancreatic cancer

Abstract This project aims to test the hypothesis that epigenetic modulatory drugs (EMD) and GVAX, a GM-CSF-secreting whole tumor cell vaccine, are capable of altering the inflammatory environment of pancreatic ductal adenocarcinoma (PDAC) and sensitizing it to checkpoint blocking agents. Recently the use of antibody therapy targeting immune checkpoints, such as CTLA-4 and PD-1, has become a major focus of cancer immunotherapy. In responsive patients, these therapies have resulted in long-term control of chemotherapy-resistant disease. The most compelling activity has been seen in the minority of patients with immunogenic tumors where T cell infiltration naturally occurs. These benefits are not observed in non-immunogenic tumors, such as PDAC, with low expression of tumor-associated antigens (TAA) and a lack of intrinsic T cell infiltrates. Therapies that can alter the tumor microenvironment (TME) and allow infiltration of effector T cells, decrease immunosuppressive cells, and stimulate TAA expression may convert non-immunogenic tumors into cancers sensitive to checkpoint inhibitors. Recent work with EMDs has shown that they are capable of altering the immunogenicity of the TME by inducing the expression of cancer testis antigens as well as increasing tumor cell expression of MHC class II and decreasing Tregs in the TME. Additionally, GVAX has been shown to induce tertiary lymphoid aggregates within the TME of patients with PDAC. We are testing the hypothesis that treatment with EMDs and GVAX can sensitize the inflammatory environment of PDAC to checkpoint blockade inhibition by evaluating changes in immune cell function within the TME via flow cytometry, immunohistochemistry, and gene expression array. We are using a murine model of hepatic metastases of pancreatic cancer which involves injecting syngeneic pancreatic tumor cells into the spleen followed by a hemisplenectomy, resulting in the consistent formation of hepatic metastases that can be monitored by ultrasound. We have evaluated entinostat, a histone deacetylase inhibitor, in combination with GVAX which induces T cell responses, and demonstrated a significant increase in survival when compared with either agent alone. Flow cytometric analysis of the cells infiltrating the TME shows that the combination of entinostat and GVAX causes a significant increase in CD4+ T cell infiltration as well as a shift from an M-MDSC dominant to a more G-MDSC dominant myeloid population. Current studies aim to elucidate the functionality of the MDSC population as well as identify potential changes in the T helper cell subsets via flow cytometry. Additionally, future studies will evaluate changes within checkpoint blockade pathways via flow cytometry and gene expression array to identify pathways that require further modulation to enhance antitumor responses. Citation Format: Brian Christmas, Blake Scott, Todd Armstrong, Nilofer Azad, Elizabeth Jaffee. Epigenetic modulation of the tumor microenvironment enhances vaccine induced T cell responses in a murine model of pancreatic cancer [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 1686. doi:10.1158/1538-7445.AM2017-1686

Risk assessment based on the Risk Index for Serious Adverse Events (SAEs) in phase I trials.

e14032 Background: Although patients (pts) in phase I trials may have expectations about their chance to benefit, they sometimes experience serious adverse events (SAEs). These events impact on their quality of life negatively as well as their clinical management and survival, if once occurred, regardless of timing of occurrence or relation to study drugs. Therefore, paying close attention for pts who are more likely to experience SAEs may be required; however, little is known about which clinical features are related to SAEs in phase I trials. The aim of this study is to construct a risk index for SAEs prediction. Methods: We collected medical records of 418 pts with solid tumor who participated in phase I trials for the first time and were treated at our hospital from January 2011 to December 2015. The time to first SAE (TTS), defined as the time from registration to first SAE, was analyzed. Stepwise Cox regression model was applied to screen out the factors to build a risk index. Internal validation was performed using a bootstrap procedure. Results: Four hundred and seven pts were analyzed for building a risk index. Median age was 63 years (range 22-81). Predominant primary tumor site was gastrointestinal cancer (65.1%), followed by lung cancer (8.4%) and genitourinary cancer (5.7%). A total of 251 pts (61.7%) were treated with small molecule compounds, while 136 pts (33.4%) were treated with antibody therapy including immune therapy. A total of 101 pts (24.8%) experienced SAEs included 18 events related to study drugs. Four independent risk factors (use of antibody therapy, 60 < age < 70, higher serum albumin concentration and lower serum alkaline phosphatase concentration), identified by stepwise Cox regression model, were combined into simple ternary risk index that stratified pts into low- (n = 93), intermediate- (n = 175) and high-risk group (n = 139). Hazard ratios for high-risk and intermediate-risk relative to low-risk group and their 95% confidence intervals were 5.25 (2.64-10.42; high-risk) and 2.00 (0.99-4.07; intermediate-risk). Conclusions: Risk assessment based on the risk index for SAEs may be useful for patient management in phase I trials. Further research is needed to validate this risk index.

Role of Fc-FcγR interactions in the antitumor activity of therapeutic antibodies.

The use of antibody therapy for cancer has steadily increased in recent years and has become standard treatment for numerous tumor types. It is now appreciated that the clinical activity of these antibodies relies upon their specific interactions with Fc receptors in addition to the well-studied target-binding region. The interactions mediated by antibody Fc domains can strongly affect the functional outcome of antibody therapy. The Fc portion of an antibody defines its interaction with numerous immune cells and has become an intense area of research as selecting the optimal Fc can greatly enhance the activity as well as mechanism of action of therapeutic antibodies. Recent advances in antibody engineering have enabled the development of antibodies that have altered Fc receptor interactions to take advantage of these findings. Engineering the Fc can fulfill diverse functions such as enhancing effector function for killing of tumor cells or depletion of unwanted immune subsets, enhancing agonist receptor signaling on particular immune cells or eliminating interaction with Fc receptors to avoid cellular depletion or toxicity in normal tissues. This review highlights important data and studies examining the role of Fc-Fc receptor interactions in therapeutic antibodies with a considerations for the future of engineered antibody therapy.

Decitabine Or 5-Azacitidine Pre-Treatment Does Not Compromise The Novel Fc-Engineered Antibody Mab 33.1-Mediated ADCC Against Primary AML Blasts - A Rationale For Combination Therapy

IntroductionAcute Myeloid leukemia (AML) in patients older than 60 years is a devastating diagnosis with long-term survival rates of 10%. Elderly patients have poor survival both due to chemoresistance and presence of concomitant comorbidities rendering them ineligible for induction chemotherapy. Hence novel treatment options are warranted in this patient population. Promising activity of monoclonal antibodies such as alemtuzumab and rituximab for chronic lymphocytic leukemia (CLL) and rituximab for lymphomas has raised the potential use of antibody therapies in AML. CD33 is expressed on greater than 90% of AML blast cells while absent from all non-hematopoietic tissues. Hence CD33 is a viable target for antibody-based therapeutics in AML. Here, we tested the ex vivo efficacy of the mAb 33.1, a fully human anti-CD33 antibody Fc-engineered for increased binding to Fcγ receptors on AML cell lines and primary AML blasts. The goals of this study are to evaluate 1) the efficacy of mAb33.1 on purified allogeneic and autologous natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against primary AML Blasts; 2) to evaluate efficacy of mAb 33.1 in combination with azanucleosides (i.e. decitabine, 5-azacitidine) that are currently used in AML therapy on NK cell-mediated ADCC against primary AML blasts; and 3) to correlate the levels of surface expression of CD33 on AML blasts to the mAb 33.1 mediated ADCC. MethodsmAb 33.1 mediated NK cell activation was determined by NK degranulation as determined by CD107a induction, and ADCC was determined by standard 4-hour 51Cr-release assay. An AML cell line HL60 and a total of 15 AML blast samples were used as targets in this study. NK cells enriched from normal donor PBMC (for allogeneic assays) or sorted from AML blast samples (for autologous assays) were used as effector cells. ResultsThe mAb 33.1 induced potent ADCC activity (>40%) compared to control non-Fc engineered antibody at the concentration of 10 μg/ml in the HL60 cell line. For the AML blasts, mAb 33.1 mediated significantly higher ADCC activity when compared to the control antibody (p<0.05). The relative cytotoxicity mediated by mAb 33.1 varied among different patients, ranging from 4.4% to 65.8%. Subsequent quantification of CD33 showed that there is a positive correlation between ADCC activity and the number of surface CD33 molecules on the AML blasts. Induction of CD107a expression was also observed in both allogeneic and autologous NK cells when the blasts were labeled with mAb 33.1. Pre-treatment of the NK cells and/or target blasts with decitabine or 5-azacitidine for 48hrs, did not alter the mAb 33.1 mediated ADCC activity or CD107 induction. ConclusionmAb33.1 mediated potent ADCC activity and NK activation against AML cell lines and primary AML blasts. Both autologous and allogeneic NK cell-mediated ADCC against primary blast cells from AML patients was observed. The level of NK cell-mediated ADCC was positively associated with the levels of the surface CD33 expression on target AML blasts. Pre-treatment of either AML blasts and/or NK effector cells with Decitabine or 5-azacitidine did not compromise mAb 33.1-mediated ADCC. These pre-clinical studies support further clinical development of mAb 33.1 in combination with relevant anti-AML therapies such as decitabine or 5-azacitidine in patients with CD33 expression. Disclosures:Heider:boehringer-ingelheim: Employment.

Negative argument for debate with V. O. Emery for J Neural Transmission

Alzheimer's disease (AD) represents a major public health challenge. It is the most common cause of dementia, the worldwide prevalence of which will double every 20years in the foreseeable future. It would be good if it were possible to treat AD early to diminish its impact, but current evidence does not support early intervention. Vitamin E was no more effective than placebo in a study of vitamin E and donepezil against placebo in mild cognitive impairment (MCI). Vitamin E is associated with a higher rate of haemorrhagic events than is placebo. Neither donepezil nor galantamine has been shown to be helpful in retarding progression from MCI to AD. Gingko biloba was ineffective in delaying the onset of AD in a large prospective trial involving over 6,000 participants. Gamma secretase inhibitors have not yet been shown to retard the progression of AD and they seem to have a high incidence of adverse effects, especially rashes. Antibody therapy has not yet been shown to be helpful in the treatment of established AD, let alone its prevention. Metalloproteinase modifiers such as PBT2 may be useful AD therapies, but current evidence gives no support to their immediate use in pre-symptomatic AD. No evidence can yet be adduced to support the use of antibody therapies in MCI or early AD. Thus, it is clear that the early treatment of AD cannot be justified as yet, no matter how desirable this goal may be. Treatment of established AD with cholinesterase inhibitors and memantine, coupled with referral of interested patients to evaluative drug trials, is the best we can do at present.

Multiagent Regimens for Metastatic Colorectal Cancer: If Some Is Good, More Must Be Better

The management of patients with metastatic colorectal cancer has undergone substantial evolution over the past two decades. The advent of several new classes of therapeutics that have been approved for use in patients with colorectal cancer since the mid1990s has resulted in tangible clinical benefit, with median survival currently expected to be in excess of 20 months (1–3). In an era not so long ago, 5-fluorouracil was the sole agent with generally recognized benefit in managing patients with colorectal cancer. The use of this agent was associated with a median survival of less than 1 year. Thus, recent advances have been substantial; however, it is humbling to realize that we still have considerable room for improvement in our therapeutic armamentarium. In addition to the development of new cytotoxic agents including oxaliplatin and irinotecan along with the antibody inhibitors of vascular endothelial growth factor and the epidermal growth factor receptor, we have learned that patients with metastatic colorectal cancer should not all be treated similarly nor should the goals of therapy be singular, namely palliation, as it was in a bygone era. We have also learned that the approximately 40% of patients whose tumors contain a mutation in the KRAS oncogene will not derive benefit from the use of antibody therapy directed against epidermal growth factor receptor (4). With the introduction of modern therapeutic approaches, it has become apparent that patients with metastatic colorectal cancer can be classified into at least three broad therapeutic groups: 1) patients with organ-isolated disease (eg, liver only), who can be managed with surgical and ablative approaches with curative intent; 2) patients with organ-isolated disease, who may be “converted” to a state that is amenable to surgical and ablative approaches with curative intent; and 3) patients whose disease is so widespread or in inaccessible locations that preclude intervention with anything but palliative intent. Clearly, the goals of therapy must be considered in selecting the optimal therapeutic intervention. For patients in whom palliation is the goal, regimens that are associated with the longest survival balanced by their attendant toxicity profile may be preferred. Conversely, for patients in whom “conversion” to an operable state is the goal, regimens with the highest response rate and at least a tolerable short-term toxicity profile may be considered optimal. The report by Masi et al. (5) in this issue of the Journal details the long-term outcomes (median follow-up of 5 years) in 244 patients with metastatic colorectal cancer who were randomly assigned to treatment with either FOLFIRI or FOLFOXIRI as first-line therapy. Antibody therapy was not used with either of these regimens because the study was conducted before the widespread availability of these agents. The authors report that the use of the three-drug regimen (FOLFOXIRI) was superior to the doublet (FOLFIRI) in all measures of clinical efficacy, including response rate (60% vs 34%; P < .001), progression-free survival (9.8 vs 6.9 months; P < .001), and overall survival (22.6 vs 16.7 months; P = .026). They also report that among patients with hepatic metastases, those treated with the three-drug regimen had a greater incidence of resections with curative intent compared with those treated with the doublet (36% vs 12%; P = .017). The higher resectability rate, although determined retrospectively, presumably reflects a higher response rate achieved with the triplet regimen. Given that response is the critical factor in enabling resection with curative intent, the FOLFOXIRI regimen is certainly a strong contender as a “conversion” regimen given the available agents. However, the 60% response rate reported by Masi et al. must be considered in context with results of the Hellenic Oncology Research Group (HORG) trial, in which 283 patients were randomly assigned to either the FOLFOXIRI or FOLFIRI regimen (6). Souglakos et al. (6) reported that the FOLFOXIRI regimen was associated with a 43% response rate among 137 patients. Although numerically superior, this rate was not statistically significantly different from the response rate of patients treated on the control arm using FOLFIRI (33.6%) and is similar to other contemporaneously conducted trials using the FOLFIRI regimen that have been reported to have response rates in the 31%–56% range (7–11). What about the patients for whom palliation is the goal of therapy? For this population, which represents the largest proportion of patients with metastatic colorectal cancer, regimens that are associated with the best survival balanced with an acceptable toxicity profile are preferred. The trial presented by Masi et al. dem onstrates a clear advantage in progression-free survival and overall survival for the FOLFOXIRI arm, whereas the HORG trial failed to demonstrate the superiority of FOLFOXIRI over FOLFIRI for either progression-free survival (6.9 vs 8.4 months; P = .17) or overall survival (19.5 vs 21.5 months; P = .34) (6). Although the progression-free survival (9.8 months) and overall survival (23.4

The Fate and Function of Therapeutic Antiaddiction Monoclonal Antibodies across the Reproductive Cycle of Rats

During preclinical development of neuroprotective antiaddiction therapeutic monoclonal antibodies (mAbs) against phencyclidine (PCP) and (+)-methamphetamine, we discovered novel, gestation stage-specific changes in mAb disposition spanning the entire reproductive cycle of female rats. Each pharmacological change was independent of mAb dose and antigen target but was precisely coincident with transitions between the gestational trimesters, parturition, and lactation periods of the female reproductive cycle. Whereas anti-PCP mAb6B5 terminal elimination half-life (t(1/2λz)) in nonpregnant females was 6.6 ± 1.6 days, the mAb6B5 t(1/2λz) significantly changed to 3.7 ± 0.4 days, then 1.4 ± 0.1 days, then 3.0 ± 0.4 days in the second trimester, third trimester, and postpartum periods, respectively (p < 0.05 for each change). Initially, these evolving changes in mAb6B5 clearance (3.3-fold), distribution volume (1.8-fold), and elimination half-life (4.7-fold) affected our ability to sustain sufficient mAb6B5 levels to sequester PCP in the bloodstream. However, understanding the mechanisms underlying each transition allowed development of an adaptive mAb-dosing paradigm, which substantially reduced PCP levels in dam brains and fetuses throughout pregnancy. These mAb functional studies also revealed that antidrug mAbs readily cross the placenta before syncytiotrophoblast barrier maturation, demonstrating the dynamic nature of mAb pharmacokinetics in pregnancy and the importance of maintaining maternal mAb levels. These studies provide the first preclinical pregnancy model in any species for chronic mAb dosing and could have important implications for the use of antibody therapies involving blood organ barriers (such as addiction) or other chronic diseases in women of childbearing age (e.g., irritable bowel diseases, multiple sclerosis, breast cancer, rheumatoid arthritis).

Immunoglobulin G Fc receptor polymorphisms do not correlate with response to chemotherapy or clinical course in patients with follicular lymphoma

Recently, immunoglobulin G Fc receptor (FcγR) polymorphisms have been found to correlate with the clinical response to rituximab or idiotype vaccine in patients with follicular lymphoma. Two critical questions are whether the FcγR polymorphisms correlate with the clinical outcomes after chemotherapy alone in patients with follicular lymphoma and whether they can be explained by linking to underlying biology of follicular lymphoma. This is an important issue because the clinical decisions about the use of antibody therapy may be based on the FcγR polymorphisms of these patients. Here, we analyzed the FcγRIIIa 158 V/F, FcγRIIa 131 H/R, and FcγRIIb 232 I/T polymorphisms in a group of 188 patients with follicular lymphoma who were treated with chemotherapy without rituximab initially. In the current study, FcγR polymorphisms neither correlated with response rate or time to progression after induction chemotherapy, nor with time to the initial therapy or overall survival after diagnosis. Our results confirm that the correlation between FcγR polymorphisms and clinical outcome is specific to immunotherapy such as rituximab and idiotype vaccination, and not due to any effect on the underlying clinical behavior of the disease or chemotherapy response.

Antibody Therapy as a Future Treatment Option for Ebola Virus Infection

Ebola virus causes lethal hemorrhagic fever in human and nonhuman primates. Effective prophylaxis and treatment for this disease are not yet available. Antisera and monoclonal antibodies specific to Ebola virus proteins have been tested for passive immunization in experimental animal models and clinical cases, and shown to be effective in mice and guinea pigs, whereas the evidence of protective efficacy in primates, including humans, remains elusive. In this review, we focus on research relevant to prophylaxis and treatment by passive immunization, and discuss the potential use of antibody therapy for Ebola virus infection. Nevertheless, there is no doubt that a comprehensive understanding of Ebola virus pathogenesis will aid in the development of therapeutic strategies against Ebola hemorrhagic fever.

Associations between use of cyclosporine-sparing agents and outcome in kidney transplant recipients

Diltiazem, widely used as a cyclosporine-sparing agent, has been suggested to confer a benefit on graft and patient outcome in kidney transplantation related to immunomodulatory properties. Use of cyclosporine-sparing agents (CsSpA) is routinely recorded by the Australia & New Zealand Dialysis and Transplant (ANZDATA) Registry, and we used these data to examine the associations between CsSpA use and outcomes. Graft and patient survival were analyzed for a cohort of 3913 people who received kidney transplants in Australia or New Zealand between 1 April 1993 and 30 March 2001. Patients were followed to death or loss of graft function. Graft and patient survival analyses were performed using Cox proportional hazards models, including a time varying covariate for CsSpA use in analyses of graft failure. Occurrence of delayed graft function (DGF) and acute rejection also were examined as secondary outcomes. There was no difference in patient survival in the first 12 months post transplantation, but from 12 months onwards there is a survival advantage associated with CsSpA use among cadaveric donor (CD) recipients in both univariate hazard ratio (HR) 0.56, 95% CI 0.41 to 0.76, P < 0.001 and multivariate (HR 0.56, 95% CI 0.40 to 0.79, P < 0.001) analyses. This was consistent across subgroups examined. Lower rates of early graft loss (censored for death) were associated with CsSpA use [odds ratio (OR) 0.61, 95% CI 0.50 to 0.75, P < 0.0001]. Lower rates of use of antibody therapy for rejection also were observed, but not lower rates of biopsy-proven rejection. CsSpA use was associated with improved patient mortality after kidney transplantation. Whether this was a direct drug effect or due to other factors associated with diltiazem use cannot be inferred directly from these data, although several plausible mechanisms exist which might mediate a diltiazem effect.

Monoclonal antibodies

For more than 100 years, clinicians have explored the use of antibody therapy for the treatment of infectious illnesses. The initial use of antibody-based therapies consisted of serum infusions to treat certain infections. The recent developments in hybridoma and recombinant technologies have refined this use with the development of monoclonal antibodies. Monoclonal antibodies that are highly specific and can be directed toward specific pathogens, inflammatory mediators, or tissues receptors have been generated. These characteristics have made them attractive molecules for use in altering the pathogenesis of infectious syndromes leading to the development of septic shock. Experimental models of sepsis and septic shock have been used to demonstrate that monoclonal antibodies directed at specific pathogens or mediators of the proinflammatory cascade can alter or block pathways leading to irreversible shock. This development has prompted clinical trials using monoclonal antibodies aimed at improving the morbidity and mortality of patients with sepsis and the septic shock syndrome. Although clinical trials have yet to clearly define an exact therapeutic role for the use of monoclonal antibodies in altering the pathogenesis of septic shock, they remain intriguing molecules for potential preventive or adjunct therapy for sepsis. We discuss the historical, current, and future prospects of monoclonal antibody therapy in the treatment of sepsis syndromes. Copyright © 2001 by W.B. Saunders Company

Disseminated tumor cells: diagnosis, prognostic relevance, phenotyping and therapeutic strategies

The incidence of local relapse after complete (R0) resection of solid tumors is largely determined by the skill of the surgeon, whereas metastatic relapse in distant organs is caused by pre- or perioperative systemic dissemination of tumor cells. The presence of individual disseminated tumor cells--e.g., in bone marrow as indicator organ--can be detected by sensitive immunocytochemical and molecular methods and is increasingly considered as a clinically relevant prognostic indicator. In contrast to solid metastases, isolated micrometastatic tumor cells are appropriate targets for intravenously applied anti-cancer therapeutics because they are easily accessible to macromolecules and immunologic effector cells. The majority of these tumor cells appear to be nonproliferating (i.e., in the G0 phase of the cell cycle), which may explain the failure of adjuvant chemotherapy. Adjuvant therapeutic strategies aimed at quiescent tumor cells are therefore of increasing interest. This therapeutic rationale has been tested and confirmed in a randomized clinical trial using antibody 17-1A in patients with non-metastatic colorectal carcinoma (UICC stage III). The antibody therapy kills also quiescent tumor cells ("dormant cells") and is independent from a potential chemotherapy resistance of the tumor cells. As treatment for minimal residual cancer, the clinical use of antibody therapy could be envisaged in conjunction with chemotherapy, applied either in parallel or sequentially. The aim of this review is to present and discuss the current state of research in the field of diagnosis and therapy of minimal residual cancer.

Applications of molecular biology and biotechnology: antibody therapy of sepsis

The use of antibody therapy for the treatment of infections and inflammatory disease is well established. Unfortunately, clinical studies of antiendotoxin and anti-TNF monoclonal antibodies have failed to show clear physiological or survival benefit. Little information is available regarding the effect of antibodies to cytokines other than TNF in human sepsis. Limited pre-clinical data indicate that IL-6 antibodies may abrogate the effects of endotoxin infusion, but no human studies have been performed. Although both monoclonal and polyclonal antibodies have the potential to protect septic humans, at this time it is the polyclonal antibodies that have shown the greatest promise. Each type of antibody possesses specific advantages and limitations, the ultimate effectiveness of which will need to be proven in large randomized clinical trials.