Verma, Meena

Abstract Background: Follicular lymphoma is a B-cell malignancy in which tumor-immune system interactions have the potential to profoundly influence malignant cell growth. Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a negative regulator of T cell activation that can serve to dampen anti-tumor immune responses. Administration of blocking anti-CTLA-4 monoclonal antibodies has been shown to improve host resistance to immunogenic tumors and amplify the anti-tumor effects of cancer vaccines in a variety of mouse tumor models. Recently, the anti-CTLA-4 antibody ipilimumab (MDX-010) has been shown to have significant clinical activity against melanoma, prostate, and ovarian cancers, with clinical responses associated with autoimmune events. Methods: We have therefore initiated a phase I/II trial of ipilimumab, a blocking fully human monoclonal antibody to CTLA-4, in patients with relapsed or refractory follicular lymphoma (grade 1 or 2). Enrollment is stratified into 2 cohorts, with half of patients required to be previously treated with a lymphoma vaccine (idiotype or other). It is hypothesized that previously vaccinated subjects are more likely to have anti-lymphoma T cells amenable to activation by an anti-CTLA-4 antibody. Study objectives include characterization of drug safety, immunologic activity and potential clinical efficacy. Treatment consists of MDX-010 at 3 mg/kg, then monthly at 1 mg/kg x 3, with plans to escalate to 3 mg/kg monthly x 4 if tolerated. Results: To date, 12 patients have been treated and accrual to the first dose level has been completed. All patients were previously treated and the median number of prior treatment regimens was 2 (range 1–4). Eight patients had previously received rituximab and 6 patients had received prior anti-idiotype vaccines. Nine patients have completed therapy with ipilimumab and 3 patients are still receiving treatment. Ipilimumab was generally well tolerated and the most common adverse events attributed to ipilimumab in the first 9 patients include diarrhea (grade 3–3 patients, grade 1–1 patient), abdominal pain (grade 2–4, grade 1–2), anorexia (grade 2-1, grade 1 – 2), fatigue (grade 2 -2, grade 1–3, and neutropenia (grade 3-1, grade 1– 2). Among 9 patients evaluable for clinical response, 1 previously vaccinated patient had partial regression of multiple abdominal nodes, ongoing at 10+ months. T cell proliferative responses to the recall antigens tetanus toxoid and keyhole limpet hemocycanin (in idiotype-vaccinated cases) were measured pre- and post-ipilimumab. In 3 of 5 cases tested, including the patient with a clinical response, T cell proliferation to KLH and/or tetanus was significantly increased (>2-fold) one month after initiation of ipilimumab, implying expansion and/or activation of the memory T cell pool. Conclusions: Blockade of CTLA-4 signaling using ipilimumab is well tolerated at the dose used thus far in this ongoing study and has anti-tumor activity in patients with follicular B-cell lymphoma. Further evaluation of the efficacy of ipilimumab at this and higher doses is therefore warranted.

Abstract Purpose: The growth of non–Hodgkin lymphomas can be influenced by tumor–immune system interactions. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell activation that serves to dampen antitumor immune responses. Blocking anti–CTLA-4 monoclonal antibodies improves host resistance to immunogenic tumors, and the anti–CTLA-4 antibody ipilimumab (MDX-010) has clinical activity against melanoma, prostate, and ovarian cancers. Experimental Design: We did a phase I trial of ipilimumab in patients with relapsed/refractory B-cell lymphoma to evaluate safety, immunologic activity, and potential clinical efficacy. Treatment consisted of ipilimumab at 3 mg/kg and then monthly at 1 mg/kg × 3 months (dose level 1), with subsequent escalation to 3 mg/kg monthly × 4 months (dose level 2). Results: Eighteen patients were treated, 12 at the lower dose level and 6 at the higher dose level. Ipilimumab was generally well tolerated, with common adverse events attributed to it, including diarrhea, headache, abdominal pain, anorexia, fatigue, neutropenia, and thrombocytopenia. Two patients had clinical responses; one patient with diffuse large B-cell lymphoma had an ongoing complete response (>31 months), and one with follicular lymphoma had a partial response lasting 19 months. In 5 of 16 cases tested (31%), T-cell proliferation to recall antigens was significantly increased (>2-fold) after ipilimumab therapy. Conclusions: Blockade of CTLA-4 signaling with the use of ipilimumab is well tolerated at the doses used and has antitumor activity in patients with B-cell lymphoma. Further evaluation of ipilimumab alone or in combination with other agents in B-cell lymphoma patients is therefore warranted. (Clin Cancer Res 2009;15(20):6446–53)