Idiotypic Vaccination of Patients with Relapsed Follicular Lymphoma Using a Novel Vaccine Formulation Including a Tobacco Plant-Produced Tumor Specific Idiotype

Abstract 1649

Idiotypic vaccination has shown evidence of biological efficacy, clinical efficacy and clinical benefit in some subsets of patients with follicular lymphoma. A phase-I clinical trial is currently being conducted to assess safety and immunogenicity of a novel, recombinant idiotype vaccine in which the idiotype protein is produced in tobacco plants. Previous animal and clinical studies with plant-produced single-chain variable fragment lymphoma vaccines have demonstrated specific immunogenicity and safety. However, the expression levels of such fragments were highly variable and required complex engineering of the linkers. Moreover, the downstream processing could not be built around standard methods like protein A affinity capture. Our novel vaccine manufacturing process by magnICON^R technology is devoid of such shortcomings and allows consistent and efficient expression in plants of idiotype-containing, whole immunoglobulins. Safety and tolerability of the novel vaccine formulation is the subject of this report.

Patients eligible for the study are those with relapsed follicular lymphoma whose prior treatment has included rituximab. Patients receive salvage therapy with bendamustine and prednisone. Use of rituximab is prohibited on this trial due to the prolonged B-cell depletion that characteristically follows its administration. Subjects enrolled in the study who achieve and maintain either a complete (CR) or partial (PR) response for at least 4 months following BP therapy undergo idiotype vaccination.

Six patients have received a variable number of monthly doses of the novel, first-in-human, magnICON^R produced idiotype vaccine. Each dose includes a conjugate of 0.5 mg of idiotype and 0.5 mg of keyhole limpet hemocyanin on day 1. A dose of 0.125mg of GM-CSF is administered with the idiotype vaccine on day 1 and alone subcutaneously at the same injection site on day 2 through 4. Each vaccination cycle is repeated every four weeks. The vaccination schedule as defined by the protocol outlines eight monthly vaccination cycles followed by four bi-monthly vaccination cycles for a total of 12 vaccinations. No patient has yet completed the entire vaccination protocol and no patient has relapsed/progressed while receiving vaccine.

Two patients have received eight vaccinations. The remaining four patients have received five, four, two and one vaccination, respectively. The patient who received two vaccinations was removed from the study after the development of progressive multifocal leukoencephalopathy Undefined symptoms had appeared prior to the initiation of vaccine and PML was subsequently attributed to previous, prolonged maintenance treatment with rituximab received prior to the enrollment in this clinical trial.

Toxicity data are available for 28 doses of idiotype vaccine. There has been no grade 4–5 hematologic and non-hematologic toxicity. Grade 3 non-hematologic toxicity was recorded in 1/6 (17%) patients and in 1/28 (4%) cycles, respectively, consisting of generalized pain during one day. Grade 1–2 non-hematologic toxicities were recorded in all six patients and virtually in all cycles. The most common of them were fatigue, pain at the injection site, myalgia, diarrhea, headache and generalized pain. Grade 3 hematologic toxicity was recorded in 2/6 (33%) patients and in 2/28 (7%) cycles, respectively, and consisted predominantly of leucopenia. Grade 1–2 hematologic toxicities were common, most often consisting of anemia and thrombocytopenia.

These preliminary data indicate that this novel idiotype vaccine is well tolerated in patients with relapsed follicular lymphoma following chemotherapy with BP. Studies of vaccine-induced humoral and cellular immune responses are ongoing. Results will be updated at the time of the meeting.

The authors wish to acknowledge Drs. Ralph Heaven, Larry Barker, Jairo Olivares, Thomas Anderson, Carl Chakmakjian, Barry Cooper, Amir Faridi, Vinay Jain, Pankaj Khandelwal, Janice Marshall, Anton Melnyk, Robert Mennel, James Turner.