Personalized Cancer Vaccine with Atezolizumab Shows Promise in Advanced Solid Tumors

The personalized cancer vaccine RO7198457 in combination with atezolizumab (Tecentriq) induced significant levels of neoantigen-specific immune responses with a manageable safety profile in patients with locally advanced or metastatic solid tumors, according to phase 1b clinical trial results presented at the AACR Virtual Annual Meeting II.

Neoantigens that arise from somatic mutations can be promising targets for cancer immunotherapy because they are recognized by the immune system as foreign. “Most of these mutated new antigens are not shared between patients,” Juanita Lopez, MB, BChir, PhD, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research in London, said during a press briefing held ahead of the meeting. “Therefore, targeted new antigen specific therapy requires an individualized approach.”

RO7198457, a messenger RNA (mRNA)-based cancer vaccine that is manufactured on a per-patient basis, is produced by sequencing tumor and blood samples and identifying tumor- specific neoantigens. Up to 20 neoantigens are selected for the corresponding mRNA to be generate before being compressed into a liposomal formulation to enable intravenous administration, “preferentially to antigen presenting cells, including dendritic cells in the spleen,” Lopez said.

The mRNA stimulates the immune system and encodes the neoantigens to stimulate an antitumor immune response. “

In dose escalation portion of the study, Lopez and colleagues administered 8 doses of RO7198457, ranging from 15-50 μg, in weekly and bi-weekly intervals during the 12-week induction stage and every 24 weeks during the maintenance stage plus 1200 mg of atezolizumab on day 1 of each 21-day cycle (n = 132).

To be included in the trial, patients had to be aged 18 or older, with advanced or recurrent solid tumors, a life expectancy of 12 weeks or more, and an ECOG score of 1 or more.

Patients were diagnosed with non-small cell lung cancer, melanoma, renal cell carcinoma, bladder cancer, triple-negative breast cancer, and serial biopsy select solid tumors. The median number of prior therapies was 3 (range, 1-11), which included 39% of patients who received prior immunotherapy. The majority of patients had low levels of PD-L1 expression, including 93% of patients with <5% PD-L1 expression on tumor cells and 79% of patients with <5% expression on immune cells.

The primary end point of the study was safety and tolerability. Secondary end points included maximum tolerated dose (MTD), determining the highest dose with acceptable toxicity, pharmacodynamic activity, and preliminary anti-tumor activity.

The median number of RO7198457 doses received was 8.

In total, 16% of patients discontinued treatment because of progressive disease prior to completing 6 weeks of therapy. Most adverse events (AEs) were grade 1/2, including infusion related reaction/cytokine release syndrome (CRS), fatigue, nausea, and diarrhea. Infusion related reaction/CRS were temporary and reversible. No dose-limited toxicities occurred.

Seven patients (5%) discontinued treatment due to AEs related to the study drugs.

The researchers detected ex vivo T-cell responses in almost 73% of patients (n = 63). There was a median 2.6neoantigen-specific responses (range, 1-9); however, ex vivo data was not available for all vaccine targets because of limited material availability and T-cell fitness, Lopez said.

CD4 and CD8 T-cell responses were detected in 14 patients. Induction of pro-inflammatory cytokines with each dosing appeared to be similar to findings from phase 1a of the trial.

One complete response was observed in a patient with rectal cancer as well as 1 partial response in a patient with triple negative breast cancer (TNBC). The patient with TNBC was previously treated with anti PD-1 therapy and entered the study with visual and lymph node metastasis that all shrank or disappeared after receiving induction treat, Lopez said. “In this patient, we observed the induction and enhancement of 2 new antigen immune responses by ex vivo. One of the de novo CD8 responses was confirmed using MHC multiple analysis with a magnitude of new antigen specific T cells reaching 2.2%,” she added. “At the peak of the response, this patient remains well on study after one and a half years.”

Moreover, preliminary evidence suggested there was infiltration of the vaccine that stimulated T cells in the tumors.

Lopez noted that in vitro stimulation ELISPOT as a more sensitive measure for immune responses to RO7198457 is ongoing.

Elaine R. Mardia, PhD, FAACR, co-executive director and endowed chair at the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, commented on the study, commending the unique study design. “Dr. Lopez and colleagues from cancer centers in Europe, Canada, and US conducted a phase 1b clinical trial with a very unique trial design, namely, combining a new antigen mRNA-based vaccine that includes specific targets unique to each patient or combination with atezolizumab,” she said. “The unique trial design that they presented combines dosing of the vaccine with dosing of the anti PDL-1 antibody and differ significantly from the handful of patients that have been described earlier in the literature.”

Reference:

Lopez JS, Camidge R, Iafolla M, et al. A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumab in patients with locally advanced or metastatic solid tumors. Presented at: AACR Virtual Annual Meeting II; June 22-24, 2020.