Current Research in Neurosurgery: Amy Heimberger, M.D.
Glioma, immunotherapy, EGFRvIII, STAT3, microglia
Our laboratory research program is focused on glioma-mediated immune suppression and central nervous system (CNS) malignancy immune therapeutic targeted approaches. One of our first immune therapeutic strategies that was taken from bench to bedside was a peptide vaccine that induces the immune system to target the epidermal growth factor variant III receptor expressed on the malignant gliomas (Clin Cancer Res 9(11):4247-4254, Sept, 2003). The phase II clinical trial “A complimentary trial of an immunotherapy vaccine against tumor-specific EGFRvIII (ACTIVATE)” a cooperative study with Dr. John Sampson at Duke University Medical Center, demonstrated a median survival of 26 months – nearly double for the stand of care. Among recurrent tumors evaluated by immunohistochemistry, 100% no longer expressed the EGFRvIII, suggesting immunological activation eliminated EGFRvIII-expressing cells, as well as one potential mechanism of treatment failure (J Clin Oncol 28(31):4670-3, 11/2010, see below graphs). The ACTIVATE clinical trial was before the establishment of standard of care (temozolomide). So as to not deprive patients of this therapeutic regimen, we therefore developed a novel strategy of incorporating temozolomide (TMZ) with the peptide vaccine that enhances immunological responses, refuting conventional dogma that chemotherapy is antagonistic to immunotherapy.
(A) Progression-free survival (PFS). Above, top: The median PFS from histologic diagnosis in the patients who had been vaccinated (n = 18; solid blue line) was 14.2 months (95% CI, 9.9 to 17.6 months). Dotted blue lines show 95% CIs. Bottom: In the temozolomide (TMZ) -treated historical cohort (n = 17; gold line), the median PFS was 6.3 months (95% CI, 4.1 to 9.0 months). The PFS of patients who had been vaccinated compares favorably with that of the TMZ-treated cohort before (P = .013) and after (P = .041) adjustment for age and Karnofsky performance status (KPS).
(B) Overall survival (OS). Above, top: The median survival of patients who had been vaccinated (n = 18; solid blue line) was 26.0 months (95% CI, 21.0 to 47.7 months;). Dotted blue lines show 95% CIs. Bottom: In the TMZ-treated historical cohort (n = 17; gold line), the median survival was 15.0 months (95% CI, 11.4 to 19.7 months). The OS of patients who had been vaccinated compares favorably with that of the TMZ-treated cohort before (P = .002) and after (P = .001) adjustment for age and KPS. EGFRVIII, epidermal growth factor receptor variant III.
A second phase II, multi-center trial was undertaken (ACT II) that demonstrated that despite TMZ induced profound lymphopenia, that potent anti-tumor immune response could be generated. This therapeutic strategy has now been incorporated extensively by other researchers conducting immunotherapy clinical trials. In 2006, the EGFRvIII peptide was licensed to Celldex Therapeutics, and a third Phase II clinical trial (ACT III) sponsored by Celldex was conducted at 31 participating sites demonstrated similar efficacy as ACTIVATE and ACTII. The definitive phase III registration trial is now proceeding in 2012. These clinical trials have been featured in Newsweek and on the CBS Evening News.
More recently, the laboratory has been focusing on the signal transducer and activator of transcription 3 (STAT3) as a key transcription factor that drives the fundamental components of malignancy and metastasis/invasion. Our laboratory has shown that STAT3 is over expressed in the vast majority of gliomas and is a negative prognostic marker for survival in malignant glioma patients (Clin Cancer Res 14(24):8228-8235, 2008). We have shown this pathway is key to glioma-mediated immune suppression and upon reversal can result in significant anti-tumor immune responses (Cancer Res 67(20):9630-9636, 2007; Clin Cancer Res 14(18):5759-5768, 2008; Neuro-Oncology 12(11):1113-25 2010). The STAT3 pathway also supports glioma cancer stem cell growth and immune suppression that can be markedly inhibited with STAT3 blockade (Clin Cancer Res 16(2):461-73, Jan 15, 2010; Mol Cancer Ther 9(1):67-78, Jan, 2010). Many investigators believe that without targeting the cancer stem cell subpopulation therapeutically, tumors will continue to persist and recur. In collaboration with Waldemar Priebe, we have devised and tested a potent and specific inhibitor of STAT3 – WP1066 (Clin Cancer Res 14(18):5759-5768, 2008) that exerts potent therapeutic efficacy in murine models (Clin Cancer Res 14(18):5759-5768, 2008; Clinical Cancer Research 16(23):5722-33, Dec. 1, 2010). We are intending to begin clinical trials of WP1066 for melanoma patients with CNS metastasis and patients with malignant gliomas in the next 18 months upon completion of the IND.
In addition to clinical trials and translational studies, we also investigate the biology and immune properties of gliomas obtained directly from the operative theater. Specifically, we have shown that tumor-associated microglia/macrophages do not participate in anti-tumor immune responses but rather assist in potentiating gliomagenesis via STAT3. We are now evaluating how microRNAs can modulate the immune responses to gliomas and are intending to exploit this type of approach for the next generation of therapeutics. As a result of our contributions to the field, Dr Heimberger has been named as a recipient of the Presidential Early Career Award for Scientists and Engineers (PECASE) - the only faculty member at MDACC to have ever been recognized in this manner by the White House.