To evaluate in patients with advanced colorectal cancer (CRC) three treatment regimens of oral capecitabine in order to select the most appropriate regimen for testing in phase III.
Three ...capecitabine schedules were evaluated in a randomized phase II design: arm A, 1,331 mg/m(2)/d bid continuously; arm B, 2,510 mg/m(2)/d bid intermittently (2 weeks on/1 week off); and arm C, 1,657 mg/m(2)/d plus oral leucovorin 60 mg/d bid intermittently (2 weeks on/1 week off).
One hundred nine patients were randomized; 39 patients were assessable for efficacy in arm A, 34 in arm B, and 35 in arm C. Patient characteristics were balanced in the arms. Confirmed tumor responses (partial response PR + complete response CR) were reported for eight patients with two CRs (21%; 95% confidence interval CI, 9% to 36%) in arm A, eight patients with one CR (24%; 95% CI, 11% to 41%) in arm B, and eight patients with two CRs (23%; 95% CI, 10% to 40%) in arm C. Median times to progression (TTP) in arms A, B, and C were 127, 230, and 165 days, respectively. Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome. There was no grade 3 or 4 marrow toxicity.
Capecitabine offers a new, effective treatment option as an oral single agent in advanced CRC. Promising overall response rates were reported for all three regimens. The addition of leucovorin to the intermittent regimen had no marked effect on tumor response or median TTP. The intermittent single-agent capecitabine schedule is proposed for phase III evaluation, based on considerations of toxicity, dose-intensity, response rate, and TTP.
The intracellular pathways that induce the differentiation of naïve B cells into antibody-secreting plasma cells remain poorly defined. A new study now provides surprising evidence that the ...activation of extracellular signal-regulated kinase (ERK) is pivotal for inducing the transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp-1), which is required for plasma cell differentiation. Consequently, ERK-deficient B cells were unable to generate plasma cells effectively. This is an unexpected result, because previous work has shown that ERK signaling functions chiefly to induce cell division, whereas plasma cells are considered to be nondividing, terminally differentiated cells. This finding not only reveals an important signaling pathway that underlies antibody-mediated immunity but also raises important questions about the varying roles that ERK, and perhaps other kinases, may play in different biological contexts.
To maintain Ab titers, individual plasma cells must survive for extended periods, perhaps even for the life of the host. Although it is clear that plasma cell survival requires cell extrinsic ...signals, the nature and source of these signals remains open for debate. It is commonly postulated that plasma cells only gain access to these signals within specialized regulatory microenvironments, or niches, in the bone marrow or in the gut. In this review we discuss current concepts and information surrounding plasma cell survival niches, and consider two opposing models to explain long-term serologic immunity.
B‐cell genesis in the bone marrow declines with advancing age. In this review, we discuss our current understanding of why B‐cell production rates decline with age with a special emphasis on why ...age‐related factors might target very early lymphoid precursors. We consider the impact of aging on cytokine responsiveness and how current models for lineage relationships for very early B‐ and T‐cell precursors might influence interpretations of experiments addressing age‐associated declines in B‐ and T‐cell differentiation. This discussion centers on the notion that aging affects events associated with the process by which hematopoietic stem cells are guided toward the B‐cell pathway. Finally, we present a model in which the age‐associated loss of early B‐cell precursors is linked to suboptimal function of key transcriptional regulators of very early B‐cell development.
Antibody‐secreting plasma cells are a central component of short‐ and long‐term adaptive immunity. Yet, many fundamental questions about how activated B cells decide to yield functional plasma cells ...have yet to be answered. Likewise, the biochemical processes underpinning the ability of plasma cells to generate and secrete large numbers of antibodies, the capacity of some plasma cell to sustain antibody secretion, presumably without interruption, for decades, and the capacity of long‐lived plasma cells to avoid apoptosis despite the high‐energy demands associated with sustained robust antibody synthesis and secretion each remain mysterious processes. Our objective here is to review what is currently known about these processes with an emphasis on the earliest phases of plasma cell genesis. Along the way, we will work toward developing a model that ties the biochemistry of plasma cell function and survival. The chief idea imbedded in this model is that progress toward understanding plasma cell survival mechanisms may require increased focus on the unique cell autonomous processes inherent in plasma cell differentiation and function.
Summary
The purpose of this article is to review the role of extrafollicular and T‐cell independent antibody responses in humoral immunity. We consider two interrelated questions: (a) do T‐cell ...independent antibody responses dominated by IgM and/or IgA play unique functions in immunity and homeostasis; and (b) is it typical for these responses to result in lifelong protection? In addressing these questions, we consider the established advantages of T‐cell driven responses including the unique role played by germinal center reactions in these responses, and contrast the processes and outcomes of germinal center‐centric responses with germinal center‐ and T‐cell independent antibodies. We suggest that T‐independent and other extrafollicular responses contribute substantially to highly stable antibody repertoires in both the serum and the intestine, providing relatively constitutive humoral barriers with the collective dual function of protecting against invading pathogens and regulating the composition of non‐pathogenic microbial communities.
To maintain antibody titers individual plasma cells must survive for extended periods, perhaps even for the life of the host. While it is clear that plasma cell survival requires cell extrinsic ...signals, the nature and source of these signals remains open for debate. It is commonly postulated that plasma cells only gain access to these signals within specialized regulatory microenvironments, or niches, in the bone marrow or in the gut. Here we discuss current concepts and information surrounding plasma cell survival niches, and consider two opposing models to explain long-term serologic immunity.
Despite new immunotherapies aimed at B and T cells, plasma cells and their lifelong antibody secretion constitute a major immune barrier to long‐term graft survival. In this mini‐review, we survey ...the recent advances that have been made in the biology and immunometabolism of long‐lived plasma cells, and outline aspects of plasma cell function that can be exploited for clinical benefit in recipients of solid organ transplants. A handful of ongoing studies are already targeting plasma cells to achieve desensitization and reduce the alloantibody burden in individuals posttransplant. In reviewing the recent strides made in our understanding of the molecular basis of plasma cell survival, we will place our discussions in the context of existing preclinical and clinical studies.
The authors review recent advances in the biology and immunometabolism of plasma cells and outline aspects of plasma cell function that can be exploited for clinical benefit in recipients of solid organ transplants.
B cells and dendritic cells (DCs) each develop from poorly described progenitor cells in the bone marrow (BM). Although a subset of DCs has been proposed to arise from lymphoid progenitors, a common ...developmental pathway for B cells and BM-derived DCs has not been clearly identified. To address this possibility, we performed a comprehensive analysis of DC differentiative potential among lymphoid and B lymphoid progenitor populations in adult mouse BM. We found that both the common lymphoid progenitors (CLPs), shown here and elsewhere to give rise exclusively to lymphocytes, and a down-stream early B-lineage precursor population devoid of T and NK cell precursor potential each give rise to DCs when exposed to the appropriate cytokines. This result contrasts with more mature B-lineage precursors, all of which failed to give rise to detectable numbers of DCs. Significantly, both CLP and early B-lineage-derived DCs acquired several surface markers associated with functional DCs, and CLP-derived DCs readily induced proliferation of allogeneic CD4(+) T cells. Surprisingly, however, DC differentiation from both lymphoid-restricted progenitors was accompanied by up-regulation of CD11b expression, a cell surface molecule normally restricted to myeloid lineage cells including putative myeloid DCs. Together, these data demonstrate that loss of DC developmental potential is the final step in B-lineage commitment and thus reveals a previously unrecognized link between early B cell and DC ontogeny.
Substance P and the neurokinin-1 (NK-1) receptor are implicated in chronic refractory cough pathophysiology. We assessed the efficacy and safety of orvepitant, a brain-penetrant NK-1 antagonist, in ...an open-label study in CRC patients with chronic refractory cough.
Thirteen patients with daytime cough frequency >3 to <250 coughs/h took orvepitant 30 mg once daily for 4 weeks. Objective cough frequency was measured over 24 h at baseline and weeks 1, 4, and 8. The primary end point was change from Baseline in daytime cough frequency at week 4. Secondary end points included cough severity visual analog scale (VAS) score, global ratings of change for cough frequency and severity, and Cough-specific Quality of Life Questionnaire score.
All patients completed the study. Mean baseline cough frequency was 71.4/h. A statistically and clinically significant improvement in objective daytime cough frequency was observed at week 4: reduction from baseline of 18.9 (26%) coughs/h (95% CI, 9.6-28.3; P < .001). This effect was apparent at week 1 (reduction from baseline of 27.0 38% coughs/h 95% CI, 11.4-42.7; P = .001) and sustained after drug discontinuation at week 8 (reduction from baseline of 20.4 29% coughs/h 95% CI, 3.2-37.5; P = .020). Statistically significant improvements were seen for severity VAS and quality of life. Orvepitant was safe and well-tolerated.
Orvepitant resulted in a significant and sustained improvement in objective cough frequency, severity VAS, and quality of life; appeared safe; and merits further clinical investigation.
EU Clinical Trials Register; No.: 2014-003947-36; URL: www.clinicaltrialsregister.eu.
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