Areas of Research
- Brain and CNS Tumor Research
- Immunology Research
- Immunotherapy Research
The Brain Tumor Immunology laboratory research program is focused on glioma-mediated immune suppression and central nervous system (CNS) malignancy immune therapeutic targeted approaches.
Key Immune Therapeutic Strategies
One of the laboratory's 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 (EGFRvIII) receptor expressed on the malignant gliomas. The phase II clinical trial – referred to as ACTIVATE – was a cooperative study with John Sampson, M.D. at Duke University Medical Center. It demonstrated a median survival of 26 months – nearly double the stand of care. Among recurrent tumors evaluated by immunohistochemistry, 100% no longer expressed the EGFRvIII, suggesting immunological activation eliminated EGFRvIII-expressing cells and was a potential mechanism of treatment failure.
The ACTIVATE clinical trial was before the establishment of the current standard of care – temozolomide (TMZ). So as to not deprive patients of this therapeutic regimen, our researchers 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 second phase II, multi-center trial called ACT II demonstrated 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. A third phase II clinical trial called ACT III, sponsored by Celldex, was conducted at 31 participating sites and demonstrated similar efficacy as ACTIVATE and ACTII. The definitive phase III registration trial is now underway. These clinical trials have been featured in Newsweek and on the CBS Evening News.
The Fundamental Signals of Malignancy
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. We have shown this pathway is key to glioma-mediated immune suppression and upon reversal can result in significant anti-tumor immune responses.
The STAT3 pathway also supports glioma cancer stem cell growth and immune suppression that can be markedly inhibited with STAT3 blockade. 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 – that exerts potent therapeutic efficacy in murine models. 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.
Biology and Immune Properties
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, lab director Amy Heimberger, M.D., has been named as a recipient of the Presidential Early Career Award for Scientists in Engineers (PECASE) - the only faculty member at MD Anderson to have ever been recognized in this manner by the White House.