Clinical Trials

The Cancer Immunobiology Center is an active participant in FDA-approved clinical trials. Many clinical trials have been completed and four have been approved by the FDA and are in various stages of completion.

(UT Southwestern participants shown in bold)

Trial 1

The use of an anti-CD25 immunotoxin (IT) to eliminate alloreactive T cells. Four clinical trials using anti-CD25 IT to eliminate alloreactive T cells have been initiated with three different investigators: Dr. Fisher in France, Dr. Brenner in Houston, and Dr. Barrett at the NIH. All three trials use an anti-CD25 IT to deplete alloreactive T cells prior to stem cell transplantation for leukemia.

The objectives of the protocols are to determine whether depletion of alloreactive cells leads to less GVHD, more rapid immune recovery, and loss of graft vs. leukemia activity. The trials at the three sites are similar but are open to different types of patients and use different methods of in vitro allodepletion.

The trial in France has been completed and published. In summary, the trial was a success in that no severe GVHD was observed in 20 patients. The results have been published. (Andre-Schmutz, I., Le Deist, F., Hacein-Bey, S., Vitetta, E., Schindler, J., Chedeville, G., Vilmer, E., Fischer, A. and Cavazzana-Calvo, M. Immune Reconstitution Without Graft-Versus-Host Disease After Haemopoietic Stem-Cell Transplantation: A Phase ½ Study, Lancet, 360:130-137, 2002.)
The trial at the NCI has been completed. Results of the trial showed a marked improvement (decrease) in rate of severe GVHD over historical controls. The results of the study have been published. (Solomon, S.R., Mielke, S., Savani, B.N., Montero, A., Wisch, L., Childs, R., Hensel, N., Schindler, J., Ghetie, V., Leitman, S.F., Mai, T., Carter, C.S., Kurlander, R., Read, E.J., Vitetta, E.S., Barrett, A.J. Selective depletion of alloreactive donor lymphocytes – a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplant. Blood, 106: 1123-1129, 2005.)
The trial in Houston has accrued 20 patients. One patient had a Grade IV skin event that was either a drug reaction or GVHD. The results have been published. (1. Amrolia, P., Mucioli-Casadei, G., Yvon, E., Huls, H., Sili, U., Wieder, D., Bollard, C., Michalek, J., Ghetie, V., Heslop, H., Molldrem, J., Rooney, C., Schindler, J., Vitetta, E., and Brenner, M. Selective depletion of alloreactive T cells without loss of anti-viral or anti-leukemic responses. Blood 104:6, 1605, 2004. 2. Savellano, MD, Pogue, B.W., Hoopes, J.P., Vitetta, E.S., Paulsen, K.D. Multi-epitope HER2 targeting enhances photoimmunotherapy of HER2-overexpressing cancer cells with pyropheophorbide-a immunoconjugates. Cancer Research, 65(14) 6371-6379, 2005. 3. Amrolia, P.J., Muccioli-Casadei, G., Hulsa, H., Adams, S., Durett, A., Gee, A., Yvon, E., Weiss, A., Cobbold, M., Gaspar, H.B., Rooney, C., Kuehnle, I., Ghetie, V., Schindler, J., Krance, R., Heslop, H.E., Veys, P., Vitetta, E., and Brenner, M.K. Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplant. Blood, 108: 1797-1808, 2006.)
The 4th trial is a study exploring the administration % of CD25+ allodepleted cells to recipients of haploidentical stem cell transplants. In this study, the number of cells will be increased beyond the highest level tested in the prior study. A suicide gene will be added to the allodepleted cells. This will allow depletion of these cells, should the higher number lead to GVHD. Three patients have been enrolled. No severe GVHD has occurred.

Trial 2

ITs against CD19 and 22 (Combotox) are effective in killing cells from a variety of B cell tumors, including Pre-B-ALL from pediatric patients. We have demonstrated that this strategy works ex vivo and have recently completed a Phase I multicenter clinical trial to determine whether this strategy is safe in relapsed patients. This study was highly successful with three complete responses and an overall response rate of 53 percent. This study has been published. (Herrera, H., Bostrom, B., Gore, G., Sandler, S., Lew, G., Schlegel, P.G., Aquino, V., Vitetta, E., Schindler, J. A Phase I Study of Combotox in Pediatric Patients with Refractory B-Lineage, JPHO,31(12):936-941,2009.)

A Phase 2 study investigating a schedule of six doses per cycle rather than three has been approved and will start when funding has been obtained. Because of the success in pediatric ALL, we have begun a trial in adult ALL. Seventeen patients have been enrolled: four at UT Southwestern, 11 at Albert Einstein in New York, and two at MD Anderson in Houston. The study is complete is and being evaluated.

Trial 3

A Pilot Clinical Trial of a Recombinant Ricin Vaccine in Normal Humans. We have generated a recombinant (r) RTA with two amino acid substitutions that disrupt its ribotoxic site (Y80A) and its VLS-inducing site (V76M). This mutant rRTA (named RiVax) was expressed and produced in E. coli and purified. When RiVax was injected intramuscularly (IM) into mice it protected them against a ricin challenge of 10 LD50s. Preclinical studies in both mice and rabbits demonstrated that RiVax was safe.

Based on these results, we have now conducted a pilot clinical trial in humans under an investigational new drug application (IND) submitted to the FDA. In this study, three groups of five normal volunteers were injected three times at monthly intervals with 10, 33 or 100 mg of RiVax. The vaccine was safe and elicited ricin-neutralizing antibodies in one of five individuals in the low dose group, four of five in the intermediate dose group, and five of five in the high dose group. The results have been published. (Vitetta, E.S., Smallshaw, J.E., Coleman, E., Jafri, H., Foster, C., Munford, R., and Schindler, J. D pilot clinical trial of a recombinant ricin vaccine in normal humans. PNAS 103:7 2268-2273, 2006.)

A second clinical trial with RiVax with alum started in 2008 and will be completed in 2012. The objective is to determine whether the addition of alum results in higher serum concentration of neutralizing anti-RTA antibody and/or longer lasting serum levels of antibody. There are three dose groups in this study. All volunteers have been entered. The volunteers in the first two dose levels have been followed for a year, and the third dose group is still being vaccinated and tested. The vaccine is safe and has elicited neutralizing antibodies.

Trial 4

Depletion of regulatory T cells with an immunotoxin directed against CD25 (RFT5-dgA).

Melanoma: We have carried out a study with Dr. Rosenberg at the NCI in patients with metastatic melanoma using RFT5-dgA. RFT5-dgA is being used to eliminate CD25+ T reg cells which protect tumors by preventing recognition of their tumor-associated antigens. Six patients have been treated and T regs were depleted by greater than 75 percent. This study has been published. (Powell, D J., Attia, P., Ghetie, V., Schindler, J., Vitetta, E.S., Rosenberg, S.A. Partial reduction of human FOXP3+ CD4 T cells in vivo following CD25-directed recombinant immunotoxin administration, J. Immunotherapy,31(2) 189-198, 2007.)
ALL. We have completed one Phase I study using RFT5-dgA in adult patients with ALL. Other studies are in the planning stage.