Eradication of minimal disease in severe combined immunodeficient mice with disseminated Daudi lymphoma using chemotherapy and an immunotoxin cocktail

Abstract

Severe combined immunodeficient (SCID) mice injected intravenously with a human Burkitt's lymphoma cell line (Daudi) develop disseminated lymphoma (SCID/Daudi), which is fatal in 100% of the mice. Early treatment of these mice with either an immunotoxin (IT) cocktail (consisting of anti-CD19-ricin A chain plus anti-CD22-ricin A chain) or chemotherapy significantly prolonged survival but was not curative. Combination therapy with the IT cocktail and any one of three chemotherapeutic drugs (doxorubicin, cytoxan, or camptothecin) cured the mice. Cure was demonstrated by both histopathologic examination of treated mice and, more importantly, by adoptive transfer of cells from organs of the cured mice to naive SCID mice where 100 tumor cells would have caused disease in the recipients. These results provide a strong rationale for combining IT therapy with conventional chemotherapy in the treatment of B-cell neoplasia.

A Comparison of the Anti-Tumor Effects of a Chimeric versus Murine Anti-CD19 Immunotoxins on Human B Cell Lymphoma and Pre-B Acute Lymphoblastic Leukemia Cell Lines

“…Previous studies have shown that an anti-CD19 IT, HD37-dgRTA, is effective in prolonging the survival of SCID mice xenografted with human pre-B ALL or NHL tumors either alone or in combination with an anti-CD22 IT and/or chemotherapy [ 18 , 19 , 20 , 21 ]. Phase I clinical trials in humans with lymphoma and leukemia have demonstrated the anti-tumor efficacy of HD37-dgRTA either alone or in combination with an anti-CD22 IT [ 22 , 23 , 24 ].…”

“…The treatment groups were as follows: (1) PBS, pH 7.4; (2) 4.7 μg/g HD37-rRTA; (3) 4.7 μg/g cHD37-rRTA; (4) 4.7 μg/g HD37-dgRTA; and (5) 4.7 μg/g RFT5-dgRTA. The dose for the IT treatment was 40% of the LD 50 of HD37-dgRTA based on previous studies [ 17 , 20 ]. Mice were followed daily and were sacrificed at the onset of paralysis, a clinical symptom which accurately predicts death.…”

“…In vitro , the anti-CD19 IT, HD37-dgRTA, is effective in killing Burkitt’s lymphoma cell lines, pre-B ALL cell lines and leukemic cells from children with pre-B ALL [16,17]. In vivo , HD37-dgRTA prolonged the survival of SCID mice that had been injected with human non-Hodgkin’s lymphoma (NHL) cells or pre-B ALL cells compared with the survival of control mice injected with saline or an isotype-matched control IT [ 18 , 19 , 20 , 21 ]. Treatment with a mixture of HD37-dgRTA and RFB4-dgRTA, an anti CD22 IT, was more effective than either IT alone [ 21 ].…”