Purpose: Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8 + T-cell immune responses, and modulation of CD4 + CD25 + FoxP3 + regulatory T-cell (Treg) numbers were secondary end points. Experimental Design: Three patients with colon cancer, four with non^Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles. Results: Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specificT-cell responses was observed after therapy. Tregs as detected by expression of CD4+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion. Conclusions: Ipilimumab treatment depressedTreg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8 + T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.

Objective To assess the efficacy and safety of a 24-week course of abatacept in the treatment of active lupus nephritis. An additional exploratory objective was to assess the potential of abatacept to induce ‘clinical tolerance’, defined as sustained clinical quiescence of lupus nephritis after discontinuation of immunosuppressive therapy. Methods Patients (n=134) with active lupus nephritis were studied in a randomized, double-blind phase II add-on trial in which they received either abatacept or placebo in conjunction with the Euro-Lupus regimen of low-dose cyclophosphamide followed by azathioprine. The primary efficacy outcome was the frequency of complete response (CR) at week 24. Thereafter, patients who met either complete or partial response criteria continued blinded treatment through week 52. During this phase of the study, subjects in the abatacept treatment group who had achieved CR status at week 24 discontinued immunosuppressive therapy other than prednisone (10 mg/d). Results There were no statistically significant differences between groups with respect to the primary outcome or any of the secondary outcomes, including measures of safety. Thirty-three percent of subjects in the treatment group and 31% of subjects in the control group achieved CR status at week 24. Fifty percent of subjects in the treatment group who met CR criteria and therefore discontinued immunosuppressive therapy at week 24 maintained their CR status through week 52. Conclusion The addition of abatacept to a regimen of cyclophosphamide followed by azathioprine did not improve the outcome of lupus nephritis at either 24 or 52 weeks. No worrisome safety signals were encountered.

Objective. To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN). Methods. In a multicenter, randomized, open-label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group) or with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients' peripheral blood were analyzed by flow cytometry. Results. Treatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/μl in the RCB group versus 11 cells/μl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with impaired maturation of naive B cells and enhanced censoring of autoreactive B cells. Conclusion. The addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN. ClinicalTrials.gov identifier: NCT02260934.

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Background Costimulatory blockade of T lymphocytes with the CTLA4-Ig fusion protein abatacept could be an effective treatment for the immune mediated neuroinflammatory disease relapsing-remitting multiple sclerosis (RRMS). Objective To evaluate efficacy and safety of abatacept in RRMS. Methods ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) was a phase II, randomized, double-blind, placebo-controlled, multi-center trial. Sixty-five of 123 planned participants with RRMS were randomized to monthly intravenous infusions of abatacept or placebo for 24 weeks in a 2:1 ratio, switched to the opposite treatment at 28 weeks, and received their final dose of study medication at 52 weeks. Enrollment was closed early due to slow accrual. The primary endpoint was the mean number of new gadolinium-enhancing (Gd+) lesions obtained on magnetic resonance imaging (MRI) scans performed every 4 weeks. Results No statistically significant differences were observed in mean number of new Gd+ MRI lesions between the abatacept and placebo groups. No statistically significant differences were observed in other MRI and clinical parameters of RRMS disease activity. Abatacept was well tolerated. Conclusion The ACCLAIM study did not demonstrate efficacy of abatacept in reducing the number of new Gd+ MRI lesions, or clinical measures of disease activity in RRMS.