Strong attack: new immunotherapy and double immunocombination therapy, late-stage solid tumor treatment new direction!

AACR is one of the oldest and largest cancer research associations in the world, which leads the current international early research frontier and direction in the field of cancer.During the second meeting of the 2020 AACR line last year, two early studies on the combination of two new immunotherapies were published in the field of advanced solid tumors.Background: tigit (T cell immune receptor with Ig and ITIM domains) is a novel immunosuppressive checkpoint expressed on activated T cells and NK cells.in preclinical studies, the inhibition of tigit and PD-L1 / PD-1 pathway at the same time can improve the anti-tumor activity compared with single use of any drug.tiragolumab (Tira or mtig7192a) is a humanized IgG1 monoclonal antibody (mAb), which can bind with tigit to prevent its interaction with ligand PVR (CD155).this is the first dose escalation study to evaluate the preliminary safety and antitumor activity of tiragolumab combined with atilizumab for advanced solid tumors.methods: the study included advanced tumors in ECoG PS 0-1 and no standard treatment was available or ineffective.patients received tiragolumab (IV q3w) (phase ia incremental dose) or combined with atilizumab (1200 mg IV q3w) (phase IB incremental dose) to determine the maximum tolerable dose (MTD) until the disease progressed or intolerable toxicity developed or the patient / investigator decided to withdraw.endpoints included safety and tolerance, pharmacokinetics (PK), pharmacodynamics and antitumor activity.results: as of April 2019, a total of 73 cancer patients (24 in stage IA and 49 in stage IB) had been treated.the median age of patients with stage IA and stage IB was 60 years old and 54 years old, respectively. 29% and 27% of patients with ECoG PS score of 0, and 67% and 57% of patients who had received more than three treatments in the past.no dose limiting toxicity (DLT) was observed.at different doses, the treatment-related adverse events were 67% (stage IA) and 59% (stage IB), and the adverse events of grade 3 or above were 4%. The most common AE were fatigue (38%, stage IA) and anemia (31%, stage IB).in the phase ia study, stable disease duration was observed for more than 4 months (n = 4).in the phase IB study, 3 patients responded, all of them were PD-L1 positive tumors, including 2 cases of non-small cell lung cancer (NSCLC) (1 case of Cr, 1 case of PR), 1 case of head and neck squamous cell carcinoma (PR), and 2 cases of patients had not received immunotherapy before.therefore, a dose amplification cohort was added in patients with PD-L1 positive in stage IB who had not received immunotherapy.in the metastatic NSCLC amplification cohort (n = 14), Orr was 50%, in which 1 patient achieved CR, 6 patients achieved PR, and DCR was 79%, with similar safety. conclusion: tiragolumab is well tolerated and safe at all dose levels. in PD-L1 positive tumors without immunotherapy (including NSCLC), tiragolumab combined with atilizumab showed preliminary antitumor activity. boost tumor immune response, ro7198457 combined with atilizumab is effective in patients with low expression of PD-L1! Background: new antigens produced by somatic mutations are targets of cancer immunotherapy, and can be recognized as exogenous by immune system. ro7198457 is a kind of RNA liposome individualized inest (tumor specific immunotherapy) that can stimulate T cells to respond to new antigens. the researchers conducted the first phase IB clinical trial to evaluate the safety and efficacy of ro7198457 combined with atilizumab in the treatment of advanced or metastatic solid tumors. methods: ro7198457 contained up to 20 tumor specific antigen epitopes. During 12 weeks of induction therapy and 24 weeks of maintenance therapy, 9 doses of ro7198457 were given weekly, with an interval of two weeks, and 1 200 mg of atilizumab was given on the first day of the 21 day cycle. results: a total of 132 patients were included in the study. The dose range of ro7198457 was 15-50 μ G. the most common tumor types were NSCLC, triple negative breast cancer (TNBC), melanoma and colorectal cancer (CRC). the median number of previous treatment lines was 3. 39% of patients received immunotherapy in the past. PD-L1 expression was low in most patients (93% of patients had PD-L1 expression in tumor cells & lt; 5%, and 79% of patients had PD-1 expression in immune cells & lt; 5%). the median dose of ro7198457 was 8, and 16% of patients discontinued treatment due to disease progression (PD) before completing 6 weeks of treatment. most adverse events (AE) were grade 1-2. ≥ 15% of patients had adverse events including transfusion related response (IRR), cytokine release syndrome (CRS), fatigue, nausea and diarrhea. IRR and CRS were transient and reversible, mainly manifested as grade 1-2 chills and fever, without DLT. 7 patients (5%) terminated treatment due to adverse events related to the study drug. a new antigen-specific T cell response induced by ro7198457 was observed in 37 / 49 (77%) patients. up to 6% of CD8 + T cells stained with MHC had a memory phenotype. in the tumor tissue biopsy after treatment, we detected the T cells that targeted a variety of new antigens induced by ro7198457. of the 108 patients, 9 patients responded with orr of 8%, including 1 patient achieving Cr and 53 patients achieving SD (49%). conclusion: ro7198457 combined with atilizumab has controllable safety, which is consistent with the mechanism of action. The combination therapy can induce obvious new antigen-specific immune response. currently, a phase II study is exploring the efficacy and safety of ro7198457 combined with pabolizumab in the first-line treatment of melanoma. References: 1. Ct302 - phase IA / IB dose escalation study of the anti tigit anti body tiragolumab as a single agent and in combination with atezolizumab in patients with advanced solid tumors2, in combination with atezolizumab in patients with locally advanced or metastatic solid tumors