CASPALLO: Allodepleted T Cells Transduced With Inducible Caspase 9 Suicide Gene

Summary

Patients are being asked to participate in this study because they will be receiving a stem cell transplant as treatment for their disease. As part of the stem cell transplant, they will be given very strong doses of chemotherapy, which will kill off all their existing stem cells. Stem cells are created in the bone marrow. They grow into different types of blood cells that we need, including red blood cells, white blood cells, and platelets. We have identified a close relative of the patients whose stem cells are not a perfect match for the patient, but can be used. This type of transplant is called "allogeneic", meaning that the cells come from a donor. With this type of donor who is not a perfect match, there is typically an increased risk of developing graft-versus-host disease (GvHD) and a longer delay in the recovery of the immune system. GvHD is a serious and sometimes fatal side effect of stem cell transplant. GvHD occurs when the new donor cells recognize that the body tissues of the patient are different from those of the donor. In the laboratory, we have seen that cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called AP1903. To get the iCasp9 into the T cells, we insert it using a virus called a retrovirus that has been made for this study. The drug (AP1903) that will be used to "activate" the iCasp9 is an experimental drug that has been tested in a study in normal donors, with no bad side effects. We hope we can use this drug to kill the T cells. Other drugs that kill or damage T cells have helped GvHD in many studies. However we do not yet know whether AP1903 will kill T cells in humans, even though it has worked in our experimental studies on human cells in animals. Nor do we know whether killing the T cells will help the GvHD. Because of this uncertainty, patients who develop significant GvHD will also receive standard therapy for this complication, in addition to the experimental drug. We hope that having this safety switch in the T cells will let us give higher doses of T cells that will make the immune system recover faster. These specially treated "suicide gene" T cells are an investigational product not approved by the Food and Drug Administration.

Timeline

Start

2008-12

Primary completion

2011-11

Completion

2027-07

Publications

• Chang EC, Liu H, West JA, Zhou X, Dakhova O, Wheeler DA, Heslop HE, Brenner MK, Dotti G. Clonal Dynamics In Vivo of Virus Integration Sites of T Cells Expressing a Safety Switch. Mol Ther. 2016 Apr;24(4):736-45. doi: 10.1038/mt.2015.217. Epub 2015 Dec 7.
• Zhou X, Di Stasi A, Brenner MK. iCaspase 9 Suicide Gene System. Methods Mol Biol. 2015;1317:87-105. doi: 10.1007/978-1-4939-2727-2_6.
• Zhou X, Di Stasi A, Tey SK, Krance RA, Martinez C, Leung KS, Durett AG, Wu MF, Liu H, Leen AM, Savoldo B, Lin YF, Grilley BJ, Gee AP, Spencer DM, Rooney CM, Heslop HE, Brenner MK, Dotti G. Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. Blood. 2014 Jun 19;123(25):3895-905. doi: 10.1182/blood-2014-01-551671. Epub 2014 Apr 21.
• Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, Liu H, Cruz CR, Savoldo B, Gee AP, Schindler J, Krance RA, Heslop HE, Spencer DM, Rooney CM, Brenner MK. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011 Nov 3;365(18):1673-83. doi: 10.1056/NEJMoa1106152.

Drugs

Indications