Investigational Vaccine TG4050 Shows Early Clinical Benefit in HPV– Head and Neck Cancers

News
Article

Phase 1 data of TG4050 elicited tumor-specific immune responses that resulted in low relapse rates in patients with resected HPV–negative head and neck cancers.

Oliver Lantz, MD, PhD, a clinical immunologist and researcher at Institut Curie in Paris, France

Oliver Lantz, MD, PhD

When given after surgery and adjuvant chemoradiotherapy, the personalized neoantigen vaccine TG4050 elicited tumor-specific immune responses that resulted in low relapse rates in patients with resected human papillomavirus (HPV)–negative head and neck cancers, according to data from a phase 1 study (NCT04183166) presented during the 2024 AACR Annual Meeting.1,2

At a median follow-up of 18.6 months, all evaluable patients who were treated with the vaccine immediately after standard-of-care adjuvant chemoradiotherapy (n = 16; arm A) were still in remission. Of those who entered into the observation arm (n = 16; arm B), 3 experienced disease relapse after 6.2, 8.8, and 18.5 months.

Moreover, immune responses were evaluated in 16 vaccinated patients in arm A and 1 vaccinated patient in arm B. Sixteen patients demonstrated evidence of activated neoantigen-specific T cells; these T cells had not been present before the administration of TG4050, which suggests that they were induced by the vaccine. Moreover, upon vaccination, the number of these T cells quickly increased and continued to be stable for up to 7 months post receipt of the vaccine.

“Immunogenic epitopes were identified in all patients allowing the manufacturing of individualized vaccines. Polyepitopic responses were induced over the course of vaccination in 16 of 17 patients using stringent testing conditions. T-cell response was maintained over time, 211 days after initiation of treatment,” Oliver Lantz, MD, PhD, a clinical immunologist and researcher at Institut Curie in Paris, France, stated in a press briefing during the meeting. “Clinical outcomes in vaccinated patients [are] promising, with no relapse in high-risk patients receiving the vaccine post-primary treatment vs 3 relapses in patients no receiving the vaccine.”

By leveraging a nonpathogenic form of poxvirus, TG4050 can deliver 30 personalized neoantigens that activate and expand antitumor T cells.2 Investigators hypothesized that the vaccine could potentially prime an adaptive immune response against tumor antigens and prevent relapse in patients with resected head and neck cancers.

The Modified Vaccinia virus Ankara (MVA) vector induces broad, specific, and durable immune response, according to Lantz. It also has an “excellent safety profile” with “proven immunogenicity in challenging immune contexture,” he added.1 “The choice of the 30 neoantigens present in the vectors have been selected using artificial intelligence and machine learning by NEC Laboratories America. The target indication is patients with head and neck cancer, and it’s being used in the adjuvant setting to prevent relapse. It’s the only neoantigen cancer vaccine targeting this indication, and it has the potential to be used in other settings, [like the perioperative setting].”

The trial enrolled patients with completely resected, stage III or IV, HPV-negative squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx.2 After undergoing surgery, completing treatment with standard chemoradiotherapy, and achieving a complete response of approximately 90%, they were randomly assigned 1:1 to receive TG4050 immediately (arm A) or upon disease relapse (arm B). Patients received the vaccine subcutaneously weekly for the duration of 6 weeks followed by every 3 weeks for up to 20 total doses. After experiencing recurrence, patients in both arms went on to receive the vaccine combined with SOC, which included checkpoint blockers.1

When looking at adaptive immune response following vaccination, Lantz reported that “Despite low mutational burden, immunogenic targets could be selected in silico leading to de novo responses as well as amplifications of pre-existing immunoreactivities.” He added that CD4-positive and CD8-positive responses were observed in 16 of 17 evaluable patients who were vaccinated with TG4050.

Moreover, the vaccine elicited an epitope-specific response against 33% of targeted mutations, and most (80%) immunoreactivities that were detected post vaccination were not detectable at baseline.

Lantz added that at day 64, the absolute number and frequency of tetramer-specific T cells substantially increased vs baseline. At least 1 tumor-specific CD8-positive T-cell response was elicited or amplified by the vaccination in 6 of 7 patients who were assessed. Ultimately, “TG4050 elicited unambiguous CD8-positive T-cell responses toward tumor antigens,” according to Lantz.

“More importantly, you can see that the frequency [of antigen-specific T cells] increased after vaccination and remains at a steady level up to 8 months after treatment,” Lantz explained. The maximum was reached at day 43 or day 64 and there continued to be a high frequency during the boosting period. In fact, “persisting vaccine responses [were observed] during the whole monitoring period,” he said.

Investigators also conducted a T-cell receptor (TCR) sequencing or single-cell RNA sequencing VDJ (variable, diversity, and joining) analysis of tetramer-sorted cells, in which they evaluated the systemic clonal expansions of tumor-infiltrating lymphocyte (TILs) or the transcriptome of vaccine-specific lymphocytes following vaccination, respectively.2 “Some of the TCRs specific for the vaccine peptides were found several times, indicating that clonal expansions occurred after vaccination,” Lantz said.1 “Many TCRs found in the tumor at baseline were expanded in the blood 64 days after vaccination.”

Adverse effects reported with the vaccine were reportedly mild to moderate.2 The most common treatment-related toxicity was injection site reaction. “Our findings indicate that TG4050 is safe and promotes an immune response against several neoantigens in most patients,” Lantz said in a press release of the data.

Study limitations included small sample size, short follow-up, and incomplete immune response data for certain patients.

Editor's Note: Dr Lantz cited the following disclosures: a shareholder in Mnemo Therapeutics and Cereus, a founder of Cereus, has received consulting fees from Biomunex, and his laboratory is a contractor of Transgen.

References

  1. Lalanne A, Jamet C, Delord JP, et al. Personalized vaccine TG4050 induces Polyepitopic immune responses against private neoantigens in resected HPV-negative head and neck cancers. Presented at: Presented at the 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract LB401.
  2. Investigational personalized vaccine provides clinical benefit for some patients with resected head and neck cancers. News release. AACR. April 9, 2024. Accessed April 9, 2024. https://aacr.ent.box.com/s/a8fie5zmoh1kf409jvydgxxhqmkgwohp
Related Videos
Sumanta Kumar Pal, MD, FASCO,
Stephen V. Liu, MD
S. Vincent Rajkumar, MD
Bernard A. Fox, PhD
Jameel Muzaffar, MD
Angela Jia, MD, PhD, of University Hospitals
Robert Wang, MD, of Fox Chase Cancer Center
Alexander Kutikov, MD, FACS, of Fox Chase Cancer Center
Roger Li, MD, of Moffitt Cancer Center