K562/GM-CSF Vaccination Reduces Tumor Burden, Including Achieving Molecular Remissions, in Chronic Myeloid Leukemia (CML) Patients with Residual Disease on Imatinib Mesylate (IM).

Despite high rates of clinical responses to IM, molecular complete responses are rare. The curative potential of allo transplantation and donor lymphocyte infusions underscores CML’s responsiveness to T cell mediated immunity. K562/GM-CSF is a tumor vaccine derived from a CML cell line that expresses several defined CML associated antigens and has been genetically engineered to produce GM-CSF. A pilot vaccination strategy was developed to determine if K562/GM-CSF immunotherapy in combination with IM could enhance T cell reactivity and clinical responses in pts having persistent, measurable disease by FISH or RT-PCR despite 1 or more years on IM. Eligible pts also had a major cytogenetic response (<35% Ph+ cells) while remaining on a stable dose of IM. Disease burden was measured serially over 12 wks prior to vaccination to assure continued measurability. Four vaccines were administered in 3 wk intervals, each consisting of 1 x 10⁸ irradiated K562/GM-CSF cells distributed over 10 sites, with or without topical 5% Imiquimod cream (a Toll-like receptor 7 agonist) used as a vaccine adjuvant. Disease burden was measured at 6 wk intervals for 9 mos from the first vaccine and specimens were banked for measurement of immune responses. BCR-ABL fusion mRNA was detected by a Taqman one step quantitative RT-PCR assay and expressed as copies of BCR-ABL mRNA per 1000 copies of ABL mRNA. The limit of detection was 1 in 20,000 copies (equivalent to 10⁻⁵ CML cells) and the assay reliably resolved differences of 10 fold or greater. A total of 19 (of 20 planned) pts have enrolled with 17 pts having completed all 4 vaccines and at least 1 disease measure since vaccine initiation. The median age is 52 (range 28–76) yrs with a median time from diagnosis to enrollment of 57 (range 16–111) mos. Pts were on IM for a median of 37 (13–53) mos prior. Thirteen previously received interferon. K562/GM-CSF vaccine was well tolerated with grade 1–2 injection site erythema and induration common. Five of 17 evaluable pts had FISH pos disease as their best previous response (BPR) with 3 becoming FISH neg post-vaccine (previous IM therapy durations of +24 mos, +43 mos, +49 mos) and 1 also becoming PCR neg (IM +24 mos). In addition, 3/12 pts whose BPR was FISH neg/PCR pos (IM therapy +15 mos, +39 mos, +51 mos) have become PCR neg post vaccine. Only 1 pt has shown disease progression having entered the study with a relatively heavy disease burden (30% FISH pos). Mean PCR measures pre-vaccine were statistically higher than post-vaccine (p=0.001). K562/GM-CSF vaccine appears to improve responses in pts on IM, including achieving complete molecular remissions, despite long durations of previous IM therapy. Measurement of immune responses to CML associated antigens is ongoing.