Research

Our laboratory co-developed with Duke University from bench-to-bedside a peptide (PEP-3-KLH/CDX-110) vaccine strategy that targets the epidermal growth factor receptor (EGFRvIII), which demonstrated induction of anti-tumor immune responses.

Related Publications:

• Heimberger AB, Crotty LE, Archer GE, Hess KR, Wikstrand CJ, Friedman AH, Friedman HS, Bigner DD, Sampson JH. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin Cancer Res 9(11):4247-4254, Sept, 2003.
• Heimberger AB, Hlatky R, Suki D, Yang D, Weinberg J, Gilbert M, Sawaya R, Aldape K. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res 11(1):1462-1466, 2005.
• Heimberger AB*, Sampson JH*, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE II, McLendon RL, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh J, Bigner DD (*Co-lead authors). Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III (EGFRvIII) peptide vaccination in patients with newly-diagnosed glioblastoma (GBM). J Clin Oncol 28(31):4670-3, 11/2010. PMCID: PMC3020702
• Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, Friedman HS, Gilbert MR, Herndon II JE, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling R, Shi W, Vredenburgh J, Bigner DD, Heimberger AB. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro-Oncology 13(3):324-33, 3/2011. PMCID: PMC3064599.

We clarified that the signal transducer and activator of transcription 3 (STAT3) pathway is a key molecular hub of gliomagenesis and tumor-mediated immune suppression and conducted the preclinical development of a novel small molecule inhibitor of STAT3, WP1066, for which Heimberger holds the IND. STAT3 has been considered an "undruggable" target until this development. This is a first-in-man agent with specificity to STAT3. This drug has been licensed to Moleculin and is now in clinical trials.

Related Publications:

• Hussain SF, Kong L-Y, Jordan J, Conrad C, Madden T, Fokt I, Priebe W, Heimberger AB. A novel small molecule inhibitor of STAT3 reverses immune tolerance in malignant glioma patients. Cancer Res 67(20):9630-9636, 2007.
• Kong L-Y, Abou-Ghazal MK, Wei J, Chakraborty A, Sun W, Qiao W, Fuller GN, Fokt I, Grimm EA, Schmittling RJ, Archer Jr GE, Sampson JH, Priebe W, Heimberger AB. A novel inhibitor of STAT3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells. Clin Cancer Res 14(18):5759-5768, 2008. PMCID: PMC2583362
• Abou-Ghazal M, Yang DS, Qiao W, Reina-Ortiz C, Wei J, Kong L-K, Fuller GN, Hiraoka N, Priebe W, Sawaya R, Heimberger AB. The incidence, correlation with tumor infiltrating inflammation, and prognosis of p-STAT3 expression in human gliomas. Clin Cancer Res 14(24):8228-8235, 2008. PMCID: PMC2605668
• Doucette TA, Kong LY, Yang Y, Ferguson SD, Yang J, Wei J, Qiao W, Fuller GN, Bhat KP, Aldape K, Priebe W, Bogler O, Heimberger AB*, Rao G* (*corresponding authors). Signal transducer and activator of transcription 3 promotes angiogenesis and drives malignant progression in glioma. Neuro-Oncology. 2012 Sep; 14(9):1136-45 [Epub 2012 Jun 29]. PMID:22753228 PMCID: PMC3424209

We have demonstrated that glioblastoma subverts the immune system to become tumor protective, especially by driving tumor-associated microglia/macrophages to assist in potentiating gliomagenesis and recruiting Tregs as well as by the intrinsic properties of cancer stem cells, which are immunosuppressive on both adaptive and innate immunity. This investigative direction has provided potential therapeutic targets/strategies and biomarker elucidation.

Related Publications:

• Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB. The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro-Oncology 8(1):261-279, 2006. PMCID: PMC1871955
• Heimberger AB, Reina-Ortiz C, Yang DS, Sun W, Abou-Ghazal M, Qiao W, Hiraoka N, Fuller GN. Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin Cancer Res 14(16):5166-5172, 2008. PMID: 18698034
• Wu A, Wei J, Kong LY, Wang Y, Priebe W, Sawaya R, Heimberger AB. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro-Oncology 12(11):1113-25, 11/2010.
• Wei J, Marisetty A, Schrand B, Gabrusiewicz K, Hashimoto Y, Ott M, Grami Z, Kong LY, Ling X, Caruso H, Zhou S, Wang YA, Fuller GN, Huse J, Gilboa E, Kang N, Huang X, Verhaak R, Li S, Heimberger AB. Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. J Clin Invest. 2019 Jan 2;129(1):137-149. PMID: 30307407.

The laboratory has elucidated the role of epigenetic microRNA regulation on tumor-mediated immune suppression, with an emphasis on potential translational therapeutic approaches. One of these strategies –miR-124 delivered with lipid nanoparticles to the immune compartment – entered clinical trials in spontaneously arising gliomas in canines.

Related Publications:

• Wei J, Wang F, Kong LY, Xu S, Doucette T, Ferguson SD, Yang Y, McEnery K, Jethwa K, Gjyshi O, Qiao W, Levine NB, Lang FF, Rao G, Fuller GN, Calin GA, Heimberger AB. miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res. 2013 Jul 1;73(13):3913-26. PMID: 23636127 PMCID: PMC3780786
• Xu S, Wei J, Wang F, Kong LY, Ling XY, Doucette T, Yang Y, Yaghi N, Qiao W, Li XG, Lang FF, Rao G, Fuller GN, Calin GA, Heimberger AB. miR-142-3p inhibits the M2 macrophage and exerts therapeutic efficacy against murine glioblastoma. J Natl Cancer Inst 106(8):pii:dju162, 06/28/2014, 8/2014. Wei J, Nduom EK, Kong LY, Hashimoto Y, Xu S, Gabrusiewicz K, Ling X, Huang N, Qiao W, Zhou S, Ivan C, Fuller GN, Gilbert MR, Overwijk W, Calin GA, Heimberger AB. MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints. Neuro Oncol. 2016 May;18(5):639-48. PMID: 26658052
• Yaghi NK, Wei J, Hashimoto Y, Kong LY, Gabrusiewicz K, Nduom EK, Ling X, Huang N, Zhou S, Kerrigan BC, Levine JM, Fajt VR, Levine G, Porter BF, Marcusson EG, Tachikawa K, Chivukula P, Webb DC, Payne JE, Heimberger AB. Immune modulatory nanoparticle therapeutics for intracerebral gliomas. Neuro Oncol. Neuro Oncol. 2016 Oct 8. PMID: 27765835

Given the recent FDA approvals of immune checkpoint inhibitors for malignancies, there is great enthusiasm for their use in glioblastoma research. Recent work in our lab has focused on clarification of potential response biomarkers and identification of glioblastoma patient subsets who may benefit.

Related Publications:

• Nduom EK, Wei J, Yaghi NK, Huang N, Kong LY, Gabrusiewicz K, Ling X, Zhou S, Ivan C, Chen JQ, Burks JK, Fuller GN, Calin GA, Conrad CA, Creasy C, Ritthipichai K, Radvanyi L, Heimberger AB. PD-L1 expression and prognostic impact in glioblastoma. Neuro Oncol. 2016 Feb;18(2):195-205. PMID: 26323609.
• de Groot J, Penas-Prado M, Alfaro-Munoz K, Hunter K, Pei BL, O'Brien B, Weathers SP, Loghin M, Kamiya Matsouka C, Yung WKA, Mandel J, Wu J, Yuan Y, Zhou S, Fuller GN, Huse J, Rao G, Weinberg JS, Prabhu SS, McCutcheon IE, Lang FF, Ferguson SD, Sawaya R, Colen R, Yadav SS, Blando J, Vence L, Allison J, Sharma P, Heimberger AB. Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages. Neuro Oncology. 2020 Apr 15;22(4):539-549; PMID: 31755915
• McGrail DJ, Pilié PG, Rashid NU, Voorwerk L, Slagter M, Kok M, Jonasch E, Khasraw M, Heimberger AB, Lim B, Ueno NT, Litton JK, Ferrarotto R, Chang JT, Moulder SL, Lin SY. High tumor mutation burden fails to predict immune checkpoint blockade across all cancer types. Ann. Oncol. 2021 May;32(5):661-672. doi: 10.1016/j.annonc.2021.02.006. Epub 2021 Mar 15. PMID: 33736924.
• Arrieta VA, Chen AX, Kane JR, Kang SJ, Kassab C, Dmello C, Zhao J, Burdett KB, Upadhyayula PS, Lee-Chang C, Shilati J, Jaishankar D, Chen L, Gould A, Zhang D, Yuan J, Zhao W, Ling X, Burks JK, Laffleur B, Amidei C, Bruce JN, Lukas RV, Yamaguchi JT, Cieremans D, Rothschild G, Basu U, McCord M, Brat DJ, Zhang H, Cooper LAD, Zhang B, Sims P, Cloughesy TF, Prins R, Canoll P, Stupp R, Heimberger AB, Horbinski C, Iwamoto FM, Rabadan R, Sonabend AM.  ERK ½ phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma. Nat Cancer. 2021 Dec;2(12):1372-1386. doi: 10.1038/s43018-021-00260-2. Epub 2021 Nov 29.PMID: 35121903