IN-VIVO TRAFFICKING OF ADOPTIVELY TRANSFERRED INTERLEUKIN-2 EXPANDED TUMOR-INFILTRATING LYMPHOCYTES AND PERIPHERAL-BLOOD LYMPHOCYTES - RESULTS OF A DOUBLE GENE MARKING TRIAL

Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and I L-2 appears to produce dramatic regressions in patients with metastati c melanoma and renal cancer. However, the in vivo mechanism of TIL fun ction is not known. We conducted an UCLA Human Subject Protection Comm ittee, Recombinant DNA Advisory Committee, and FDA-approved clinical t rial using genetically-marked TIL to test the hypothesis that these ce lls have unique, tumor-specific in vivo trafficking patterns. TIL and PBL (as a control effector cell population) were isolated and expanded in parallel in vitro in IL-2-containing medium for 4-6 wk. During the expansion, TIL and PBL were separately transduced with the amphotropi c retroviral vectors LNL6 and G1Na, Transduced TIL and PBL were coinfu sed into patients and their respective numbers measured in tumor, peri pheral blood, and normal tissues; integrated provirus could be quantit ated and distinguished by DNA PCR. Nine patients were treated (six mel anoma, three renal) and received between 4.5 X 10(8) and 1.24 X 10(10) total cells, Both ''marked'' TIL and PBL could be detected circulatin g in the peripheral blood, in some patients for up to 99 d after infus ion. Marked TIL and/or PBL could be detected in tumor biopsies in six of nine patients as early as day 6 and as late as day 99 after infusio n. No convincing pattern of preferential trafficking of TIL vs, PBL to tumor was noted. Moreover, concurrent biopsies of muscle, fat, and sk in demonstrated the presence of TIL/PBL in comparable or greater numbe rs than in tumor in five patients. The results of this double gene mar king trial provide interesting insights into the life span and traffic king of adoptively transferred lymphocytes, but do not support the hyp othesis that TIL specifically traffic to tumor deposits.