Extended Survival of Glioblastoma Patients After Chemoprotective HSC Gene Therapy
Science Translational Medicine
Jennifer E. Adair, Brian C. Beard, Grant D. Trobridge, Tobias Neff, Jason K. Rockhill, Daniel L. Silbergeld, Maciej M. Mrugala, and Hans-Peter Kiem
MRI of the brain (subject one). Axial T1 post gadolinium sequences at the level of midbrain.
A. Area on enhancement seen in the left temporal lobe at the time of initial presentation (arrow). Gross total resection was performed and histology confirmed glioblastoma, WHO grade IV.
B. Area of enhancement and surrounding edema in the left temporal lobe 6 months following diagnosis (radiographically changes were interpreted as possible pseudoprogression). Patient has already received radiotherapy, one dose of conditioning BCNU and stem cell transplantation followed by 2 cycles of temozolomide with O-6-BG when this scan was taken. Patient elected to have surgery and the enhancing abnormality was removed; histology indicated presence of necrosis along with altered, less aggressively appearing tumor. Study drugs were continued.
C. Stable disease with only faint area of linear enhancement seen at the posterior margin of the resection cavity (arrow) 12 month following initial diagnosis (6 months following 2nd craniotomy) after four additional cycles of temozolomide and O-6-BG.
MRI of the brain (subject two). Axial T1 post gadolinium images.
A. Enhancing lesion in the right parietal lobe (arrow) at the time of initial presentation.
B. First post-radiation scan, enlargement of the enhancing area and associated vasogenic edema (arrow heads) are present (radiographically imaging findings were thought to represent possible pseudoprogression).
C. Six months from the original diagnosis, after 2 cycles of temozolomide and O-6-BG, area of enhancement has enlarged but surrounding edema has diminished and patient was clinically stable.
D. Eleven months from the original diagnosis, after two additional doses of temozolomide with O-6-BG. Area of contrast enhancement is stable.
Chemotherapy is a double-edged sword. Designed to target runaway cells with uncontrolled replication – the hallmark of cancer – healthy cells of the bone marrow, gut, and even hair are also vulnerable because of their intrinsically high replication rates. This collateral damage manifests itself in the form of immunosuppression and intolerable side effects for the patient, often requiring the clinician to reduce the duration and dosage of the chemo regimen as a result. Foreseeably, this alteration of therapy reduces the efficacy of the treatment and further hinders the patient’s chances of recovery.
In this study, defeatHIV co-PI Hans-Peter Kiem of the Fred Hutchinson Cancer Research Center has led a team of researchers in demonstrating the therapeutic potential of gene-modified, chemotherapy-resistant hematopoietic stem cells (HSCs).
What, might you ask, does cancer or chemo-resistant stem cells have to do with our HIV eradication efforts?
Dr. Kiem, along with fellow defeatHIV investigators Drs. Philip Gregory and Michael Holmes, are currently leading a key defeatHIV initiative to develop and test HIV-resistant stem cells in a preclinical model (see descriptions of Projects 2 & 3). Transplant optimization in a preclinical model is essential before clinical testing in people can begin. To this end, generating high levels of the HIV-resistant stem cells following transplant will be an important component of the model optimization. If the HIV-resistant stem cells were also chemo-resistant, this would provide a distinct advantage to their expansion over healthy unmodified cells following chemotherapy.
If we can demonstrate this method of selection for HIV-resistant cells is safe and effective in the preclinical model, we will apply the technique in clinical studies involving HIV-infected individuals requiring bone marrow transplant for hematologic malignancies.
More details on our clinical studies involving HIV-infected subjects are forthcoming. Stay tuned for updates on defeatHIV.org and in our upcoming Newsletter! Subscribe here.
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