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Overcoming tumor antigen anergy in human malignancies using the novel indeolamine 2,3-dioxygenase (IDO) enzyme inhibitor, 1-methyl-D-tryptophan (1MT).

3004 Background: The limited effect of cancer immunotherapy is due to the tumor's ability to induce host anergy towards its antigens. The enzyme indoleamine 2,3-dioxygenase (IDO) is thought to play a key role in anergy induction. IDO metabolizes tryptophan (trp) into immunosuppressive metabolites such as kynurenine (kyn). The oral IDO inhibitor, 1-methyl-D-tryptophan (1MT), was studied in preclinical models. The preclinical data support the activity of 1-MT in preventing T-cell anergy in TDLN, slowing growth of LLC mouse xenografts, and synergizing with chemotherapy in regression of autochthonous breast tumors in MMTV-Neu mice. This led to a phase I first-in-man trial using 1-MT in solid tumors.


METHODS
This is a phase I study treating adults with refractory solid malignancies. Patients are treated with up to 6 consecutive 28-day cycles starting at 200mg once daily. A 3+3 dose escalation to MTD is used. PK analysis, weekly labs, and CT scans every 2 cycles were done. Correlative studies include serum kyn/trp levels, T-reg cell quantification by flow, tumor IDO expression by IHC, and humoral immune response using a proprietary tumor antigen microarray.


RESULTS
Ten pts have recieved 1-MT at 200mg daily. Tumors treated included 1 esophageal, 1 peritoneal, 3 melanomas, 2 sarcomas, and 3 NSCLC. PK results show good bioavailability and a t1/2 of 2-4 hrs. Of the 7 evaluable pts, 4 had SD and 3 had PD. Attributable toxicities were 1 case of grade 1 fatigue and 2 cases of grade 2 hypophysitis. Both cases occurred in pts who received prior immunotherapies. Six new pts without prior immunotherapy were enrolled at the 200mg dose level. Five pts remain on treatment currently. Three pts had decreased T-reg cells after treatment with 1MT and 4 pts showed marked CRP increases. One pt had increased autoantibody titers against 3 tumor antigens compared to baseline.


CONCLUSIONS
1-MT appears to be an active, orally bioavailable, and reasonably well tolerated immunomodulator at 200mg daily. Development of hypophysitis in 2 patients indicates the drug can break tolerance resulting in autoimmunity. Enrollment to the trial continues. Future trials will combine 1-MT with other immunotherapies and chemotherapies for solid tumors. [Table: see text].