Personalized Genomic Cancer Vaccine Appears Effective across Different Tumor Types

Each day, we better understand cancer's complex relationship with the immune system, and this understanding opens doors to new treatments. One such approach is neoantigen- and tumor-genome-specific immunotherapies. Below, you can find our translation of a video prepared about cancer immunology and these innovative immunotherapies.

Tumor-Specific Genomic Cancer Vaccine

A personalized genomic cancer vaccine tested in different cancer types was well tolerated and showed promising activity in a phase 1 clinical trial.

The vaccine, code-named PGV-001, was given to 13 patients with solid (organ) tumors or multiple myeloma who had a high risk of recurrence after surgery or autologous stem cell transplantation.

At the last follow-up, 4 patients were still alive with no evidence of disease and had received no subsequent treatment, 4 were alive and receiving treatment, 3 had died, and 2 had been lost to follow-up.

Dr Thomas Marron of Mount Sinai in New York presented these results in a poster at the American Association for Cancer Research Annual Meeting 2021.

Although cancer immunotherapy has revolutionized cancer treatment, we know that the overall response rate to immunotherapies remains around 30-40%. One reason may be the absence of a preexisting, primed T-cell response needed for PD-1 blockade to have a substantial effect. To address this, personalized neoantigen vaccines may help prime an enhanced immune response against tumor cells.

With this in mind, Marron and colleagues developed a vaccine administered to patients in the adjuvant (protective after primary treatment) setting: PGV-001, consisting of patient-specific synthetic neoantigen peptides.

How Is a Personalized Cancer Vaccine Developed?

The researchers synthesized PGV-001 for 15 patients with advanced cancer as follows:

Patients first underwent tumor and germline DNA sequencing and HLA typing. Bulk RNA sequencing was also performed on their tumors.

The researchers then used a computational pipeline called OpenVax to identify candidate neoantigens. Developed at Mount Sinai, this pipeline identified and prioritized candidate neoantigens using predicted MHC class I binding affinity and neoantigen abundance.

What Is a Neoantigen?

As a result of the genetic mutations they contain, cancer cells produce thousands of different new types of proteins called neoantigens. As is known, cancer develops through the accumulation of gene mutations. Very few of these mutations are "drivers." In other words, these are the mutations that actually cause cells to become cancerous.

Fighting T cells need a form of training to recognize neoantigens. This is precisely the goal of personalized cancer vaccines.

OpenVax identified an average of 71.5 neoantigens per patient (range, 7 – 193). The aim was to synthesize a maximum of 10 peptides per patient, but two patients did not have enough neoantigens.

• Related topic: Google Made a Major Investment in Personalized Cancer Vaccines

Vaccine Administration

The peptides were administered with poly-ICLC and a tetanus helper peptide over 27 weeks. Before receiving the vaccine doses, patients with solid tumors had undergone surgery as their primary treatment, and those with multiple myeloma had undergone autologous stem cell transplantation.

Most experimental personalized cancer vaccines are administered in metastatic cancers, but earlier research has suggested that immunotherapies tend to be more effective in patients with less extensive cancer spread.

The researchers therefore stated that they had developed a neoantigen vaccine for administration when patients typically have microscopic residual disease after standard treatment, such as surgery for solid tumors and bone marrow transplantation for multiple myeloma.

Feasibility, Safety, and Immunogenicity

PGV-001 was synthesized for 15 patients and administered to 13 of them. Of the 13 patients, six had head and neck squamous cell cancer, three had multiple myeloma, two had non-small cell lung cancer, one had breast cancer, and one had urothelial carcinoma.

11 patients received all 10 intended doses, and two patients received at least 8 doses.

"The vaccine was well tolerated, and only half of the patients experienced mild, grade 1 side effects," Marron said.

Transient injection-site reactions occurred in 4 patients, and grade 1 fever was reported in one patient.

Monitoring of the patients' immune responses is ongoing, but an initial analysis in one patient showed "robust responses" in CD4 and CD8 T cells, as measured by intracellular cytokine staining for interferon-gamma, tumor necrosis factor-alpha, and interleukin-2.

Marron noted that robust T-cell reactivity was seen across all 10 doses but not after the 6th dose, supporting the need for a prolonged dosing schedule.

Survival Rates and Subsequent Treatment

At an average follow-up of 880 days, four patients had no evidence of disease and had received no subsequent treatment. Of these 4 patients, one had stage IIIA non-small cell lung cancer, one had stage IVA HER-2-positive breast cancer, one had stage II urothelial carcinoma, and one had multiple myeloma.

Another 4 patients were alive and receiving subsequent treatments. Two of these patients had substantial responses to anti-PD-1 immunotherapy.

3 patients died, and recurrence of their cancers was documented in two of them. The final two patients were lost to follow-up without documented cancer recurrence.

In conclusion, the OpenVax biotechnology method appears to be a feasible approach to creating a safe, personalized cancer vaccine that could potentially be used to treat a range of tumor types.

Dr Marron said that trials incorporating neoantigens identified by the OpenVax platform were ongoing in patients with urothelial carcinoma and glioblastoma multiforme.