August 16, 2011
Genetically Engineered T Cells Kill Leukemia
Longer life thru genetic engineering.
(PHILADELPHIA) -- In a cancer treatment breakthrough 20 years in the making, researchers from the University of Pennsylvania's Abramson Cancer Center and Perelman School of Medicine have shown sustained remissions of up to a year among a small group of advanced chronic lymphocytic leukemia (CLL) patients treated with genetically engineered versions of their own T cells. The protocol, which involves removing patients' cells and modifying them in Penn's vaccine production facility, then infusing the new cells back into the patient's body following chemotherapy, provides a tumor-attack roadmap for the treatment of other cancers including those of the lung and ovaries and myeloma and melanoma. The findings, published simultaneously today in the New England Journal of Medicine and Science Translational Medicine, are the first demonstration of the use of gene transfer therapy to create "serial killer" T cells aimed at cancerous tumors.
It worked fast and better than expected.
"Within three weeks, the tumors had been blown away, in a way that was much more violent than we ever expected," said senior author Carl June, MD, director of Translational Research and a professor of Pathology and Laboratory Medicine in the Abramson Cancer Center, who led the work. "It worked much better than we thought it would."
A big improvement over existing treatments.
The results of the pilot trial of three patients are a stark contrast to existing therapies for CLL. The patients involved in the new study had few other treatment options. The only potential curative therapy would have involved a bone marrow transplant, a procedure which requires a lengthy hospitalization and carries at least a 20 percent mortality risk -- and even then offers only about a 50 percent chance of a cure, at best.
They targeted a protein on the surface of cancer cells called CD19 and they are now going to go after more cancers.
Moving forward, the team plans to test the same CD19 CAR construct in patients with other types of CD19-positive tumors, including non-Hodgkin's lymphoma and acute lymphocytic leukemia. They also plan to study the approach in pediatric leukemia patients who have failed standard therapy. Additionally, the team has engineered a CAR vector that binds to mesothelin, a protein expressed on the surface of mesothelioma cancer cells, as well as on ovarian and pancreatic cancer cells.
What I do not understand: Normal B cells in the blood also express CD19. So what happens with all the healthy B cells? How can a patient survive without them?
Any cancer with unique surface proteins is potentially targetable via this therapy. So the question in my mind: Do all cancers have unique surface proteins? Otherwise a therapy could wipe out a needed type of tissue.
Looking ahead, suppose effective anticancer treatments are developed.
They probably would be expensive, at least at first, as Moore's Law would not apply to pharmaceuticals.
So what would happen if only the rich could afford treatment?
Trips overseas for questionable treatment with dubious generics?
> Normal B cells in the blood also express CD19. So what happens with all the healthy B cells?
That's an issue. This tx did diminish normal CD19-bearing B cells, IIRC patients were given immunoglobulin boosts to make up for this. After tx ends, presumably new B cells regenerate from progenitors.
> Any cancer with unique surface proteins is potentially targetable via this therapy. Do all cancers have unique surface proteins?
No. Most do not. Cancer cells often re-express fetal or embryonic antigens that were reduced as cells matured or differentiated. But it's not necessarily an on/off thing. And often, the antigen in question is expressed by other cell types in the body.
> Otherwise a therapy could wipe out a needed type of tissue.
That's an issue. So, folks like Carl June try to pick cancers that have consistently high expression of an antigen that's otherwise rare or expressed at low levels. And, as with CD19, where "friendly fire" won't kill you.
Another potential complication is that cancers have unstable, evolving genomes. So while most cells of a typical patient's typical cancer may express high levels of antigen X, some of those cells may have mutations in both copies of gene X (or have suppressed transcription of X, etc.). Heterogeneity gets more pronounced as cancers grow and metastasize. Thus, anti-X therapy provides selective pressure that can benefit those cancer cells that no longer produce X.
Still, this could lead to a major regression of a tumor, or to a reprieve of many months or years. It could also tip the scales in favor of the body's own anti-cancer immune response. So cancer genome changes are something to consider, but not a reason to expect that a targeted approach is doomed to failure.
Oops, sorry to post again. They adapted natural killer cells, not natural killer T cells.
Co-expressions unique to cancer cells: Interesting idea. But how to attack only cells that have 2 different antigens? Can a T cell be made to only go into destructive mode if 2 different kinds of antibodies on its surface connect to a target cell?
I wonder whether an mRNA drug that only expresses in cells that have certain cancer mutations would enable the marking of cancer cells with antigens.
So then the therapeutic T cells eventually die off? Otherwise I would think the B cell attacks would continue indefinitely.
Cancers that have consistently high expression of an antigen: Any idea whether that rules out most cancers as suitable targets?
Genetic heterogeneity: If the mutants each create a different antigen variant it might make sense to identify many different variants and attack them all at once.
My impression is that to cure cancer will require targeting multiple targets at once that are each partially or fully unique to cancer cells.
As far as I know, the therapeutic T cells will not die off. The constant production of B cells with CD19 to kill will keep them going. The plus side is that relapse is less likely. If there are malignant cells, the T cell constructs will keep the population small. A smaller population is less likely to evolve around a selective pressure.
NK cells have lots of receptors promoting and inhibiting attack, so do T cells. Co-opting some receptors to cell surface features would probably allow IF, AND, and NOT responses. but this could be totally baked, if it's not, you heard it here first. One of the special things about the transgenic T cells was that they were self-stimulating with antigen binding: the construct receptor has a few domains taken from other T cell transmembrane proteins so there's signal transduction when the antibody fragment domain binds.
I'm Monday morning quarterbacking, but the MHC-independent T cells need to be controllable to some extent: build in a pathway so that some small molecule drug sends them into apoptosis or anergy.
mRNA drug, do you mean RNAi or delivering mRNA? Either way, The problems with targeting particular mutations is other mutations: cancer cells vary genetically, that variation influences phenotype variation, and they reproduce: cancers evolve. Just because a bunch of cancer cells express some protein, that doesn't mean that it's necessary. Cancer cells can lose IIRC 25-75% of their DNA, and conceptually seductive techniques, like setting off signal cascades for apoptosis or whatever, won't work because the system isn't there. That's what'll happen trying to exploit RNA gene silencing.