Desmoplastic Small Round Cell Tumors (DSRCT) are rare and aggressive pediatric soft tissue sarcomas that grow in the abdomen/pelvic area. Current treatments such as surgery, chemotherapy, and radiation inevitably lead to recurrences, resulting in a 15% 5-year survival rate. 

One promising alternative treatment is two-step pretargeted radioimmunotherapy (2-step PRIT). First, antibodies are administered to localize to the tumor, followed by a pretargeting interval that allows unbound antibodies to clear from circulation. Next, radioisotopes are administered to kill the tumor. By separating antibody and radioisotope delivery, 2-step PRIT reduces systemic toxicity from circulating radioisotopes. Hence, 2-step PRIT offers a compelling combination of safety and potency. 

2-step PRIT is optimized using radioisotope-engaging bispecific antibodies (BsAbs). These BsAbs are made up of antibody fragments smaller than conventional IgG antibodies. Their reduced size allows for faster clearance from the body and less systemic radioactive toxicity. This is further optimized by employing α-emitting isotopes as the radioactive payload, which enhances tumor specificity due to short-range radiation emission. 

We evaluated several BsAbs for 2-step PRIT against DSRCT in comparison to irinotecan and temozolomide, the standard-of-care chemotherapy. We found that these BsAbs could kill DSRCT cell line xenografts without significant hematopoietic toxicity, while irinotecan and temozolomide led to tumor recurrence, severe illness, and weight loss in mice. The mice will be monitored for six months to determine whether the treatment was truly curative.