John R. Ohlfest, Ph.D.
Departments of Pediatrics and Neurosurgery
University of Minnesota, 2004, Ph.D.
612-626-2491 - office
612-624-1195 - lab
Cancer Immunotherapy: The Ohlfest lab is focused on understanding the mechanisms
of brain tumorogenesis and immune evasion, and using this
information to improve therapeutic outcome. There are a several
projects ongoing that all relate to the central goal.
Brain Tumor Immunotherapy: Although select
patients appear to benefit from immunotherapy, there is considerable
debate about the optimal way to maximize the effectiveness
of immunotherapy. Our research aims to improve the efficacy
of tumor vaccines using several different mouse models of
glioma, an aggressive brain tumor. We are systematically optimizing
each step of the immune response that occurs following vaccination
from the innate response at the vaccination site to the effector
response in the brain. There are several ongoing projects
in this area.
- Influence of oxygen tension on tumor cell immunogenicity
- Toll-like receptor agonists as vaccine adjuvants
- Optimizing the priming of tumor-reactive T cells in the
- Understanding factors that influence lymphocyte trafficking
into the brain
- Understanding and overcoming immune suppression at the
- Requirements for antibody and NK cell response in vaccination
Requirements for Tumor Renewal and Progression:
Glioblastoma is difficult to cure by surgery because glioma
cells migrate centimeters away from the main tumor mass and
self-renew to repopulate the tumor. We have identified CD44,
a cell surface receptor for hyaluronic acid, as playing a
key role in glioma cell invasion and self-renewal. Using CD44+/+
and CD44-/- mice, we are interrogating the role CD44 plays
in the tumor recurrence, resistance to chemotherapy, and evading
the immune response. This project is made possible due to
the novel spontaneous glioma model we developed that can be
induced in any mouse strain (Cancer Res. 2009 Jan 15;69(2):431-9.).
Drug Delivery: The blood brain barrier (BBB)
restricts the influx of drugs into normal brain structures
where glioma cells typically infiltrate. The BBB has a mechanical
(size exclusion) and active mechanism (ATP-dependent drug
transporters) to exclude drugs and antibodies from entrance.
We have several projects ongoing in this area will the goal
of increasing the efficacy of drugs to treat tumors directly,
or by delivering drugs overcome immune suppression at the
- Pharmacologic inhibition of drug efflux transport at
BBB and tumor cell barriers
- Convection enhanced delivery (CED) by neurosurgical intervention
to bypass the BBB by placing catheters in the brain directly
- Improve catheter design for CED
- Chemotherapy conditioning to deplete myeloid derived
suppressor cells and regulatory T cells
Comparative Oncology: While mouse models
of brain cancer provide us with important information, they
are limited in their ability to predict human responses. Therefore
we have initiated a canine brain tumor clinical trials program.
We currently offer several clinical trials to pet owners that
are faced with the diagnosis of a brain tumor in their dog.
These treatments include anti-tumor vaccines, chemotherapy,
gene therapy, and convection enhanced delivery. Moreover,
we typically perform surgery to removal as much of the tumor
as possible; this maximizes the benefit for the dog and mimics
the human clinical situation. Because these canine tumors
are naturally arising and can be treated with human-scale
doses, the results have great relevance to human medicine.
This research program plays an instrumental role in our clinical
trial design in humans.
Clinical Research: We are actively involved
in clinical trials. Our lab has developed immunotherapy interventions
that will be tested in brain tumor patients. In addition to
developing the treatment, we also conduct immune monitoring
to measure the immune response evoked by vaccination. We use
this information to design more effective therapy.
To learn more about our lab visit www.braintumorlab.com.
Selected Recent Publications:
- Ohlfest JR, Ivics Z, Izsvák Z. 2009. Transposable
elements as plasmid-based vectors for long-term gene transfer
into tumors. Methods
Mol Biol. 542:105-16.
- Oh S, Ohlfest JR, Todhunter DA, Vallera VD, Hall WA, Chen
H, Vallera DA. 2009. Intracranial elimination of human glioblastoma
brain tumors in nude rats using the bispecific ligan-directed
toxin, DTEGF13 and convection enhanced delivery. Journal
of Neuro-Oncology. Jun 11. [Epub ahead of print]
- Wiesner SM, Decker SA, Larson JD, Ericson K, Forster C,
Gallardo J, Zamora EA, Donelson RB, Long C, Demorest ZL,
Low WC, SantaCruz K, Largaespada DA, Ohlfest JR. 2009. De
Novo Induction of genetically engineered brain tumors in
mice with plasmid DNA. Cancer
- Xiong Z, Gharagozlou S, Vengco I, Chen W and Ohlfest
JR. 2008. Effective CpG Immunotherapy of Breast Carcinoma
Prevents but Fails to Eradicate Established Brain Metastasis. Clinical
Cancer Research 14(17):5484-5493.
- Wu A, Oh S, Ericson K, Chen L, Hall WA, Champoux PE, Low
WC, and Ohlfest JR. 2008. Persistence of CD133+ Cells in
Human and Mouse Glioma Cell Lines: detailed characterization
of GL261 glioma cells with cancer stem cell-like properties. Stem
Cells and Development. Feb;17(1):173-84.
- Wu A, Oh S, Gharagozlou S, Vedi RN, Ericson K, Chen W,
Low WC, and Ohlfest JR. 2007. In Vivo Vaccination with Tumor
Cell Lysate plus CpG Oligodeoxynucleotides Eradicates Murine
- Candolfi M, Curtin JF, Nichols SW, King GD, Barcia C,
Pluhar GE, McNiel E, Ohlfest JR, Freese AB, Moore PF, Lowenstein
PR, Castro, MG. 2007. Glioblastoma Multiforme (GBM): A Comparative
Histopathological Analysis of Experimental Gliomas in Mice
and Rats with Spontaneous GBM of Dogs and Humans. Journal
of Neuro-oncology. 85:133-48.
- Oh S, Odland R, Wilson S, Kroeger KM, Liu C, Castro MG,
Lowenstein PR, Freese A, Hall WA, Ohlfest JR. 2007. Improved
distribution of small molecules and viral vectors in the
murine brain using a hollow fiber catheter. Journal
of Neurosurgery. 107(3):568-577.
- Wu A, Oh S, Ericson K, Demorest ZL, Vengco I, Gharagozlou
S, Chen W,Low WC, and Ohlfest JR. 2007. Transposon-based
Interferon Gamma Gene Transfer Overcomes Limitations of
Episomal Plasmid for Immunogene Therapy of Glioblastoma. Cancer
Gene Therapy. 14: 550-560.
- Oh S., G. Pluhar E.G., McNeil, E.A., Kroeger, K.M., Liu
C., Castro M.G., Lowenstein P.R., Freese A., and Ohlfest,
J.R.. 2007. Efficacy of Nonviral Gene Transfer into the
Canine Brain. Journal
- Candolfi M, Pluhar GE, Kroeger K, Puntel M, Curtin J,
Barcia C, Muhammad AG, Xiong W, Liu C, Mondkar S, Kuoy W,
Kang T, McNeil EA, Greese AB, Ohlfest JR, Moore P, Palmer
D, Ng P, Young JD, Lowenstein PR, Castro MG. 2007. Optimization
of adenoviral vector mediated expression in the canine brain
in vivo, and in canine glioma cells in vitro. Neuro-oncology.
- Wu A., Xiao J., Chen W., Hall W.A., Low W.C., and Ohlfest
J.R. 2007. Expression of MHC I and NK ligands on human CD133+
brain tumor cells: possible targets of immunotherapy. Journal
of Neuro-oncology. 83(2): 121-31.
- Candolfi M, Kroeger KM, Pluhar GE, Liu C, Barcia C, Bergeron
J, Puntel M, Curtin JF, McNiel EA, FreeseAB, Ohlfest JR,
Moore PF, Kuoy W, Lowenstein PR, Castro MG. 2007. Adenoviral
mediated gene transfer into the dog brain in vivo. Neurosurgery.
- Ohlfest JR, Freese AB, Largaespada DA. 2005. Nonviral
Vectors for Cancer Gene Therapy: Prospects for Integrating
Vectors and Combination Therapies. Current
Gene Therapy. 5(6):629-641.
- Ohlfest J.R., Demorest, Z.L., Mootoka, Y., Vengco, I.,
Oh, S., Chen, E., Scappaticci, F.A., Saplis, R.J., Ekker,
S.E., Low, W.C., Freese, A.B., and Largaespada, D.A. 2005.
Combinatorial antiangiogenic gene therapy by nonviral gene
transfer using the sleeping beauty transposon causes tumor
regression and improves survival in mice bearing intracranial
human glioblastoma. Mol
- Wiesner SM, Freese AB, Ohlfest JR. 2005. Emerging concepts
in glioma biology: implications for clinical protocols and
rational treatment strategies. Neurosurgical
- Ohlfest, J. R., Frandsen, J. L., Fritz, S., Lobitz, P.
D., Perkinson, S. G., Clark, K. J., Nelsestuen, G., Key,
N. S., McIvor, R. S., Hackett, P. B., and Largaespada, D.
A. 2005. Phenotypic correction and long-term expression
of factor VIII in hemophilic mice by immunotolerization
and nonviral gene transfer using the Sleeping Beauty transposon
- Ohlfest, J.R., P.D. Lobitz, S.G. Perkinson and D.A. Largaespada
2004. Integration and long-term expression in xenografted
human glioblastoma cells using a plasmid-based transposon
Ther. 10: 260-268.
Last modified on: August 26, 2009