To summarize: The authors have reported the delayed development of the tumor lysis syndrome and a complete response 3 weeks after the treatment of a case of TP53 deleted, multiply treated, CLL with his own genetically modified T-cells. They were modified to target CD19 by infecting them with a lentivirus vector expressing anti-CD19 linked to CD3-zeta and CD137 (4-1BB) signaling domains.
Genetically modified cells were present at high levels in bone marrow for at least 6 months after infusion. There was a CD19-specific immune response in bone marrow as shown by the release of cytokines and the disappearance of leukemia cells that coincided with the peak infiltration with genetically modified T-cells.
This is the first time that the tumor lysis syndrome has been caused by cellular immunotherapy. The fact that such cells can be so potent means that future clinical trials will need to be very carefully designed.
Although in B-cell lymphomas the targets for immunotherapy like this are readily available, possible targets present themselves for non-hemic cancers and this approach may have a wider application. An important feature of this approach is that no tissue matching is needed and there is no risk of GVHD, so that “off-the-shelf” lentiviral vectors might be constructed for tumors of a wide variety of histologic types.
In previous trials of redirected T-cells, objective tumor responses have been modest, and the expansion of the modified T-cells in the body has not been sustained. This limitation seems to have been overcome by incorporation of the CD137 (4-1BB) signaling domain. In this respect it seems superior to CART-19 cells incorporating a CD28 signaling domain.
The authors were surprised that the very low dose modified T-cells would result in a clinically evident antitumor response. It is possible that the chemotherapy used might have potentiated their effects, possibly by increasing engraftment and migration of the T-cells to tumor cells as well as synergizing with the T-cells to kill stressed tumor cells that would otherwise survive the chemotherapy.
Although the prolonged persistence of the modified T-cells in the blood and bone marrow of our patient might have resulted from inclusion of the 4-1BB signaling domain, another serendipitous mechanism suggests itself. There was no anti-mouse or anti-idiotype response generated, possibly from the choice of CD19 as a target. By eliminating all the CD19 positive cells it rendered impossible the chance of making specific antibodies.
Although CD19 is an attractive tumor target because it is expressed only on normal and malignant B-cells, there is concern that persistence of the modified T-cells will cause long-term B-cell deficiency. In fact, in this patient, B cells were absent from the blood and bone marrow for at least 6 months after infusion. This patient did not have recurrent infections. Targeting B-cells through CD20 with rituximab is an effective and relatively safe strategy for patients with B-cell neoplasms, and long-term B-cell lymphopenia is manageable. But CD19 is more extensively expressed than CD20. Patients treated with rituximab have been reported to have a return of B cells within months after discontinuation of therapy; this is unlikely to occur in this patient and management might be much more difficult.
Is this an important paper? Yes, because it shows the possible potency of redirected T-cell treatment.
Can it be rolled out tomorrow? No. Two other patients with advanced CLL have also received CART19 infusions according to this protocol, and although all three have had tumor responses, everybody puts their best case forward first (remember Mr Carr, the first patient treated with anti-idiotype monoclonal antibodies back in the 1980s - that treatment is no longer with us).
Can we expect clinical trials of this treatment shortly? Perhaps, or something like this. I get the impression that the final form of this treatment has not yet been optimized. There may be several more pilot studies before we see a definitive trial.
What is my verdict on it? I am excited by it but mainly because it is close to the field that I am working in, rather than as a treatment for today or even tomorrow. Remember, this is only a single case report and the remission has only lasted for about a year. We shall know more later, but it is an elegant approach to the problem. It is not a cure - yet.
I will still continue to advocate FCR for many patients and chlorambucil for some. Others will be more suited to Revlimid or to trials containg CAL-101 or PCI32765 for some time to come.
Finally, celluar therapy is extremely expensive. There will be few for whom it can be afforded, especially at present.