Cancer Immunotherapy Clinical Trials

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Recent accomplishments of our immunotherapy clinical trials include the following: More than 630,000 cases of HPV related cancer occur worldwide annually. About 15-20% of cases respond to PD-(L)1 inhibitors and about 30% respond to dual PD-L1/TGF-beta blockade including 10% of checkpoint refractory pts, but for the majority of pts with checkpoint refractory disease there is no effective standard therapy. Preclinical studies show that the combination of PDS0101, a therapeutic vaccine targeting HPV 16 E6/E7, M9241, a tumor-targeting IL-12 immunocytokine, and bintrafusp alfa (BA), a bifunctional fusion protein targeting TGF-beta and PD-L1, resulted in maximum T cell infiltration and tumor reduction compared to any 1 or 2 of these agents alone. Prior clinical data suggests that the combination is preferentially active in HPV 16+ disease. 30 pts with advanced HPV 16+ cancer were treated with PDS0101, M9241 and BA (NCT04287868). Pts received BA at 1200 mg IV q2wks, M9241 at 16.8 mcg/kg SC q4wks or 8 mcg/kg SC q2wks, and PDS0101 as two 0.5 ml SC injections q4wks. Dose reductions or skipped doses for toxicities of BA and M9241 were allowed. 5 pts had surgical resection of tumor for disease control and were censored for PD but not survival. 30 pts (9 cervical, 2 vaginal/vulvar, 6 anal, 13 oropharyngeal) were treated. 13/30 had grade 3 treatment related AEs including grade 3 anemia in 9 pts associated with grade 3 hematuria in 3 pts and grade 3 GI bleeding in 3 pts. 2 pts had grade 3 AST/ALT elevation. Grade 3 flu like symptoms and grade 3 hemophagocytic lymphohistiocytosis were each seen in 1 pt. One pt had grade 3 lymphopenia/leukopenia plus grade 4 neutropenia and one pt had grade 4 AST/ALT elevation. There were no grade 5 treatment related AEs. 7/8 (88%) pts with checkpoint naive disease had objective responses (OR) including 1 delayed response after initial PD with 4/7 (57%) responses ongoing (median 17 months follow up). 10/22 (45%) with checkpoint refractory disease have had disease reduction including 6/22 (27%) with OR and 4/6 (67%) responses ongoing (median 12 months follow up). 6/8 (75%) pts with checkpoint naive disease and 17/22 (77%) pts with checkpoint refractory disease are alive after a median of 17 and 12 months follow up respectively. For checkpoint refractory pts, M9241 dosing appears to affect response rates. 5/8 (63%) pts receiving M9241 at 16.8 mcg/kg had an OR compared to 1/14 (7%) who received M9241 at 8 mcg/kg with an OR. However, despite differences in response rates with higher vs lower M9241 dose, survival outcomes were similar irrespective of M9241 dose (p = 0.99 by Kaplan Meier analysis). The combination of PDS0101, M9241 and BA appears to have a manageable safety profile along with early evidence of clinical activity for pts with checkpoint naive and refractory advanced HPV 16+ cancer. Moreover, growing data suggest that all 3 drugs in the combination contribute to the encouraging outcomes being observed. In addition, preclinical studies have shown that the triple combination of entinostat (histone deacetylase inhibitor), M9241, and bintrafusp alfa may also have promising anti-tumor activity in checkpoint refractory disease. 7 patients with advanced checkpoint refractory HPV positive cancers who had been previously treated with PDS0101, M9241 and bintrafusp alfa (NCT04287868) and progressed went on to be treated with the combination of entinostat, M9241, and bintrafusp alfa (NCT04708470). These patients received bintrafusp alfa at 300 mg IV q 2weeks, entinostat 3 mg po weekly including a 1 week lead in of entinostat alone, and M9241 at either 4 mcg/kg SC q 2 weeks or 8 mcg/kg SC q 4weeks (based on dose escalation cohort). Pts receiving M9241 at 8 mcg/kg did not receive entinostat on the week of M9241 treatment but did on all other weeks. 7 patients with advanced checkpoint refractory HPV positive cancers (5 oropharyngeal, 1 anal, 1 neuroendocrine rectal) who had progressed on PDS0101, M9241 and bintrafusp alfa went on to receive entinostat, M9241, and bintrafusp alfa. After switching to the entinostat based triple combination, 2/7 patients had grade 3 treatment related AEs including grade 3 anemia in one patient and grade 3 leukopenia/lymphopenia in another. Otherwise, there were no grade 3 or greater treatment related AEs observed in patients switching to the entinostat based triple combination. 3/7 (43%) patients (2 oropharyngeal, 1 anal) have had tumor reduction of 28.8%, 38.3% and 42.6% by RECIST after switching to the entinostat based triple combination. Escalating doses of the triple combination of entinostat, M9241 and bintrafusp alfa continue to be evaluated in an ongoing phase I/II trial (NCT04708470). To date the triple combination appears to have a manageable safety profile along with encouraging clinical activity in patients with advanced checkpoint refractory HPV related cancers including in pts who have previously progressed on PD(L)1 inhibitor then on PDS0101, M9241 and bintrafusp alfa.