K562/GM-CSF Immunotherapy as a “Booster” Vaccine In Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a disease that is responsive to T-cell-mediated immunity. K562/granulocyte macrophage-colony stimulating factor (GM-CSF) is a vaccine derived from a CML cell line that produces GM-CSF and expresses several CML-associated antigens. An initial pilot study was performed in 19 patients in chronic phase CML who had achieved at least a major cytogenetic response on imatinib mesylate (IM) but had measurable molecular disease. The results suggested that immunotherapy resulted in a lowering tumor burden in the majority of patients (n = 13) with a total of 7 patients achieving undetectable bcr-abl levels by QT-PCR. (Smith, Clinical Cancer Research, 2010). This extension study evaluated the biologic impact of K562/GM-CSF given as a “booster” in subjects who completed the pilot study's scheduled 4 vaccinations and continued to have have persistent measurable disease or who lost their best response to the original therapy.

This is a single-institution pilot study using open-label K562/GM-CSF vaccination as a “booster” in chronic phase CML patients who were previously treated with a full 4-vaccination course of therapy and continued to have measurable CML disease. Patients were stratified as having either responded to the initial set of vaccines and had subsequent loss of response or as having had no measurable response to therapy. None experienced significant adverse events in the first set of vaccinations. “Booster” treatment consisted of 4 doses of 1 × 10⁸ irradiated K562/GM-CSF given every 3 weeks. Imatinib was continued through the study at the patients’ starting doses. Disease burden was measured using peripheral blood RT-PCR and FISH was every 3 months throughout the course of planned booster vaccinations for up to a year following the vaccination boost. Patients with evidence of advancing disease requiring adjustments to their IM dosing or those progressing to accelerated or blast phase were taken off study.

11 patients met the eligibility to receive the booster vaccinations. Mean age was 54 (range 38–78) years. Median dose of IM therapy was 600 mg daily (range 400–800 mg). The median time from final vaccination in the pilot study to first booster vaccination was 24 (range 18–24) months. Duration of follow up was a median of 36 months (range 6–42 months). In general, the trend for lower disease burden following booster vaccines was significant by Generalize Estimating Equation using all study measures (p<0.009). Seven patients (63%) achieved their lowest levels of disease burden to date at a median of 5 (range 3–39) months following the initiation of their booster vaccinations with only 1 patient losing their “best” response as defined by a 10-fold increase in PCR value. One of the responding patients who had lost her complete molecular remission and became positive for 5 consecutive PCR readings prior to starting the booster immunizations was found to be undetectable after starting the booster treatments and has maintained negative PCR after the completion of the booster series (now at 1 year post booster). Three patients, all of whom qualified for the booster vaccines as “non-responders” to the initial immunizations, went off study secondary to progression of disease. Using sera from patients on the initial pilot study, antibodies against a total of 24 newly identified CML associated antigens were detected in post-vaccination > pre-vaccination samples. Of these, 15 antigens were recognized in 2 or more subjects. The influence of the vaccine boost series on antibody titer and on the induction of antibodies to antigens not previously recognized is under study. K562/GM-CSF immunotherapy given as a “booster” vaccination was associated with the lowering tumor burdens in 7 of 11 treated patients. Ongoing efforts to identify tumor-associated antigens that may be serving as immunologic targets is ongoing.

Levitsky:HL vaccine: Patents & Royalties.