iNEST/Atezolizumab Combo Induces Neoantigen-Specific T-Cell Responses in Advanced Solid Tumors

Juanita Lopez, MB BChir, PhD

The addition of the individualized neoantigen specific immunotherapy (iNEST) RO7198457 to atezolizumab (Tecentriq) induced neoantigen-specific T-cell responses, and was found to be well tolerated in patients with advanced solid malignancies, according to preliminary results from a phase 1b study presented during a press program ahead of the 2020 AACR Virtual Annual Meeting II.^1,2

Results showed that the combination led to ex vivo T-cell responses in nearly 73% (n = 46) of the 63 patients whose peripheral blood have been evaluated to date. The median number of neoantigen-specific responses per patient was 2.6 (range, 1-9), which were both CD4+ and CD8+ T-cell responses.

“We have established that RO7198457 in combination with atezolizumab was generally well tolerated,” said Juanita Lopez, MB BChir, PhD, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, during the press program. “RO7198457 in combination with atezolizumab induced immune responses in the majority of patients, including preliminary data demonstrating the detection of neoantigen-specific T-cell responses within the tumor. The combination of RO7198457 and a checkpoint inhibitor is currently under investigation in randomized phase 2 clinical studies.”

It is known that mutated neoantigens can be recognized by the immune system as foreign, making them attractive targets for therapies; RO7198457 was designed to induce strong T-cell responses against such neoantigens. Most mutated neoantigens are dissimilar between patients; therefore, the targeting of neoantigens requires an individualized approach, Lopez explained.

RO7198457 is a messenger RNA (mRNA)-based cancer vaccine, which is developed on a per-patient basis. As part of the manufacturing process, tumor-specific antigens are detected via next-generation sequencing. Once up to 20 neoantigens are selected, the corresponding mRNA is created as part of the vaccine. This is then encapsulated in a liposomal formulation, which is then delivered to patients as an intravenous injection.

“Its proposed dual mechanism of action is innate immune stimulation and [encoding of] neoantigens,” Lopez said. “First, patients receive an intravenous injection of RNA-LPX that include 2 messenger RNA molecules, each encoding up to 10 neoantigens, which is then preferentially delivered to antigen-presenting cells, including dendritic cells in the spleen.”

RO7198457 then activates the dendritic cells by binding to toll-like receptor 7/8 with the production of proinflammatory cytokines, which leads to the upregulation of costimulatory molecules. Then, the translation of RO7198457 into a polypeptide containing the neoantigens is

processed into peptides that can be presented on MHC class I and II molecules, thereby activating CD4+ and CD8 T-cell responses.

The phase 1b trial (NCT03289962) includes a phase 1a dose-escalation phase in which investigators are evaluating RO7198457 at 5 dose levels: 25 μg 38 μg, 50 μg, 75 μg, and 100 μg. Three doses—25 μg, 38 μg, and 50 μg—were then tested in combination with 1200 mg of atezolizumab every 3 weeks. Eight doses of RO7198457 are administered in the induction phase in weekly and bi-weekly intervals, a boost in cycle 7, and followed by maintenance RO7198457 every 8 cycles thereafter. Atezolizumab is administered on day 1 of each 21-day cycle.

To be eligible for enrollment, patients must be at least 18 years of age, have advanced or recurrent solid tumors, a life expectancy of 12 weeks or longer, and an ECOG performance status of 0 or 1.

Patients are then enrolled onto indication-specific expansion cohorts, including non–small cell lung cancer and melanoma (separate cohorts for patients who previously received a checkpoint inhibitor and those who were immunotherapy–naïve), renal cell carcinoma, urothelial cancer, triple-negative breast cancer (TNBC), and serial biopsy select solid tumors. Patients across tumor types were enrolled on the dose-escalation phase regardless of PD-L1 expression or prior checkpoint inhibitor treatment.

The primary end point of the trial is safety and tolerability, and secondary outcome measures include maximum-tolerated dose, recommended phase 2 dose, pharmacodynamic activity, and preliminary antitumor activity.

To date, 144 patients with advanced solid tumors have been enrolled. The median number of prior therapies was 3, and nearly 40% of patients previously received immunotherapy. The majority of patients had low levels of PD-L1 expression on both the tumor cells and the immune cells.

Regarding safety, the combination was reported to be well tolerated; the majority of adverse events (AEs) were grade 1/2. While no dose-limiting toxicities were observed, 7 patients discontinued treatment due to treatment-related AEs.

Nine of 108 patients who had at least 1 tumor assessment responded to the combination, which demonstrated an 8% overall response rate. One complete response (CR) was reported in a patient with colorectal cancer; 53 patients (49%) had stable disease.

Preliminary data showed that the combination induces the production of cytokines that are detected post-infusion. Additionally, Lopez explained that there may be infiltration of RO7198457-stimulated T cells in the tumor, which was detected in 1 patient with rectal cancer who was treated with atezolizumab and RO7198457 at 38 μg. Induction and enhancement of 2 neoantigen immune responses by ex vivo were reported in 1 patient with TNBC.

“RO7198457 in combination with atezolizumab has modest activity in the heavily pretreated dose-escalation patient population with 1 CR observed in a [patient with] rectal cancer, and 1 partial response observed in a [patient with] triple-negative breast cancer,” said Lopez.

Ex-vivo data are not available for all vaccine targets due to limited material availability and T-cell fitness, Lopez explained.

AACR president Elaine R. Mardis, PhD, Nationwide Foundation Endowed Chair in Genomic Medicine, and co-executive director of the Institute for Genomic Medicine at Nationwide Children’s Hospital, commented on the study during the press program.

“The unique trial design that [the investigators] present combines dosing of the vaccine with dosing of the anti–PD-L1 antibody atezolizumab, and differs significantly from the handful of patients that have been described earlier in the peer-reviewed literature, wherein neoantigen vaccines of different types—including mRNA vaccines—were given to patients sometimes in combination with checkpoint blockade inhibitor therapy, but typically in the interval subsequent to the vaccine dosing, not [concurrent] vaccine dosing,” Mardis concluded.

References:

1. Lopez JS, Camidge R, Iafolla M, et al. A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumabin patients with locally advanced or metastatic solid tumors. Presented at: 2020 AACR Virtual Annual Meeting II, June 22-24, 2020; Virtual. Abstract CT301.
2. Personalized Cancer Vaccine Plus Atezolizumab Shows Clinical Activity in Patients With Advanced Solid Tumors [news release]: Philadelphia, PA. AACR. Published June 22, 2020. Accessed June 22, 2020.