Medical research using Angimmune's technology in a Phase I clinical trial
of the anti-T cell bivalent immunotoxin Resimmune™ (IND
No. 100712, clinical trial identifier NCT00611208) at Scott & White
Memorial Hospital, Temple TX under the direction of Arthur Frankel M.D., is
currently being investigated. Early results on the first 5 treated patients
were reported in Current Drug Targets, 2009, 10, 104-109,
Anti-CD3 Recombinant Diphtheria Immunotoxin Therapy of Cutaneous T Cell
Lymphoma (CTCL). These results have not established safety or clinical
efficacy. However, a number of interesting observations have been made that
will guide future studies. Several of these observations and their relevance
to mechanisms are described below. This page will be updated when additional
study results are published.
Sustained Effect Theory
This immunotoxin kills both malignant and normal T cells, however the normal T cells begin to repopulate within ten days from the periphery. This process is known as homeostatic proliferation. T cells repopulated by homeostatic proliferation may have different clonal distributions and different activities compared to previous states.1 In the study, patient number two was treated and reported as follows:
"Patient 2 is a 78-year-old male who developed CTCL in 2003 with a maculopapular
rash on his buttocks and a groin mass. Biopsy of both lesions showed T-cell
lymphoma. CT scan showed diffuse adenopathy. He received six cycles of chemotherapy
with cyclophosphamide, doxorubicin, vincristine, and methylprednisolone (CHOP
chemotherapy), but after several years the rash recurred. Biopsy again showed
CTCL. He did not have node or marrow involvement based on CT scans and bone
marrow biopsies and was staged as IB. He was treated with A-dmDT390-bisFv(UCHT1) and achieved a PR lasting one month. Following recurrence of
his skin lesions, he received no further therapy. His disease diminished spontaneously
over six months."2 Further studies
are being done to determine if this observation of a sustained effect is repeatable
in a larger population of treated patients.
The most likely theory for a sustained effect is that the anti-T cell immunotoxin acts in addition to killing malignant T cells as an immunomodulator. The immunomodulation achieves a “resetting” of the immune system upon T cell repopulation that renders the body less hospitable to the tumor. Supporting evidence for this hypothesis is the fact that in mice homeostatic repopulated T cells lose self-tolerance toward tumor antigens (Klebanoff et al., Trends Immunol, 2005, 26(2), 111-117.) This raises the possibility that anti-T cell immunotoxin may be able to function as an immune modulator for malignancies that do not uniformly express surface CD3 such as T-ALL or even malignancies with no expression of CD3 such as metastatic melanoma.
T cells repopulated by homeostatic proliferation may have different clonal distributions and different activities compared to previous states. This raises the possibility that T cell depletion followed by homeostatic repopulation may induce remissions in some T cell driven autoimmune diseases.
In a monkey model of multiple sclerosis where foreign myelin basic protein induces T cells to enter the brain causing encephalomyelitis, treatment with anti-T cell immunotoxin eliminates brain and blood T cells. When T cells repopulate in the blood, they do not reenter the brain compartment indicating that the repopulated T cells have changed their pathological characteristics (Hu et al., 1997, Cellular Immunology, 177:26).
1.) The Journal of Immunology, 2008, 180:, Homeostatic Proliferation of Lymphocytes Results in Augmented Memory-Like Function and Accelerated
2.) Current Drug Targets, 2009, 10, 104-109, Anti-CD3 Recombinant Diphtheria Immunotoxin Therapy of Cutaneous T Cell Lymphoma.