PURPOSE: A phase II trial was performed to evaluate the safety and efficacy of rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with bulky (> 10-cm lesion) relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-one patients received intravenous infusions of rituximab 375 mg/m 2 weekly for four doses. All patients had at least one prior therapy (median, three; range, one to 13) and had progressive disease at study entry. Patients were a median of 4 years from diagnosis. RESULTS: No patient had treatment discontinued because of an adverse event. No patient developed human antichimeric antibody. The overall response rate in 28 assessable patients was 43% with a median time to progression of 8.1 months (range, 4.5 to 18.6+ months) and median duration of response of 5.9 months (range, 2.8 to 12.1+ months). The average decrease in lesion size in patients who achieved a partial response was 76%, and patients with stable disease had a decrease in average lesion size of 26%. Median serum antibody concentration was higher in responders compared with nonresponders, and a negative correlation was shown between antibody concentration and tumor bulk at baseline. CONCLUSION: Rituximab single-agent outpatient therapy is safe and shows significant clinical activity in patients with bulky relapsed or refractory low-grade or follicular B-cell NHL.
Abstract A murine B cell lymphoma (38C13) was used as a model to study the induction of idiotype (Id)-specific tumor immunity. Immunization of syngeneic mice with Id protein derived from the tumor resulted in the production of anti-Id antibodies by the host and in the induction of a state of resistance to tumor growth. Tumor immunity could be established only if the Id protein was conjugated to a strongly immunogenic carrier protein such as keyhole limpet hemocyanin or thyroglobulin, and if the conjugate was administered at least 1 week prior to tumor challenge. Free Id protein, such as that present in tumor bearing animals, was found to inhibit tumor immunity in a dose-dependent manner. Although tumor immunity could be induced in animals with pre-existent serum Id protein, the expression of the immune state was inhibited by the presence of the soluble protein.
Abstract An initial panel of four syngeneic monoclonal antibodies directed against the idiotype of a murine B cell lymphoma was used to treat this tumor in vivo. The antibody in the panel of the IgG2a isotype was more effective in treatment than the other antibodies, which were of the IgG1 and IgG2b isotypes. To independently assess the role of antibody isotype in mediating antitumor effects, switch variant hybridoma families were isolated from the hybridomas secreting the less effective IgG1 and IgG2b antibodies. A family isolated from an IgG1-secreting parent consisted of IgG1-, IgG2b-, and IgG2a-secreting members, and an IgG2a variant was isolated from an IgG2b-secreting parent for another family. Antibody members of each family differed only in heavy chain composition and were the same with respect to their light chains and their affinity and specificity for idiotype. The IgG2a members of both families were superior to the other members in inhibiting tumor growth with an order of effectiveness of IgG2a greater than IgG1 greater than IgG2b. These in vivo results paralleled the abilities of these different isotype antibodies to mediate antibody-dependent cellular cytolysis in vitro. For the IgG2b----IgG2a family, in vivo treatment with the IgG2a member given i.p. after i.p. tumor challenge at one-tenth the dose of the IgG2b member was still superior to the latter. At one-hundredth the dose of the IgG2b, the IgG2a was still superior to the latter when the antibodies were given i.p. and tumors subcutaneously. These data and those showing that the clearance of these antibodies from the serum differed in only a relatively minor way indicate that the IgG2a antibodies in this system had greater antitumor effects primarily by virtue of their greater capacity for host effector interaction.
6534 Background: Relapse is a problem after ASCT for NHL. The immune system is not active early post-ASCT. Adding immunotherapy may decrease relapse and prolong survival. In an initial phase I/II trial, we determined the MTD of IL2. This dose increased the number of immune cells and expression of lytic activity against NK and LAK targets. Rituximab is a monoclonal antibody directed against CD20 on B cells. Rituximab has anti-proliferative effect, induces apoptosis and lyses tumors using Complement and ADCC. Since Rituximab's effectiveness after ASCT may be limited by poor immune function, it seemed reasonable, based on our previous trial, to study the combination of Rituximab/IL2. Methods: From 1/2000, 18 patients (indolent n=1; aggressive n=17) after ASCT for CD20+ NHL were treated with Rituximab/IL2. Patients began therapy at platelet count (untransfused) > 30,000 cells/mm3, ANC >1,000 cells/mm3, TB ≤ 2 mg/dl, SGOT/SGPT ≤ 2.5 x ULN and creatinine ≤ 2 mg/dl. Patients could not be on steroid therapy, have active infection, or have evidence of disease progression, pericardial effusion, pleural effusion or ascites. The treatment was: IL2 at 0.6x106 iu/m2/day sc for 12 weeks, followed by 1.4x106 iu/m2 sc 3 times/week for an additional 12 weeks. Rituximab was given 375 mg/m2 iv (total of four doses): beginning 1 day prior to IL2, between days 25–30, 50–55 and 75–80 of IL-2 therapy. NCI Common Toxicity Criteria were used for grading toxicity. Results: The median time to start of therapy was 74 days post-transplant (range 49–100). Four patients met early toxicity stopping rules grade 3 (infection, n=2) and grade 4 (neutropenia, n=2). Neutropenia responded to G-CSF, within 3–8 days. The infections seen were: pneumonia (n=2), oral thrush (n=2), oral herpes (n=1), UTI (n=1) and URTI (n=2). The only reoccurrence was in a mantle cell patient who stopped therapy at 4 weeks and died on day +149 post transplant. Seventeen patients remain alive with no evidence of relapse, with a median follow-up of 22 months (8–42). Conclusions: Rituximab/IL2 is well tolerated after ASCT and may decrease relapses. A randomized study is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech
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