With Zero Five-Year Recurrences, the Emerging Tumor Vaccine Brings Hope of Cure

Undoubtedly, vaccines are one of the most significant milestone inventions in mankind’s fight against diseases, and they have also played an essential role in the treatment of cancer.

If we say PD-1/PD-L1 inhibitors are the first “trump card” of immunotherapy, and adoptive cellular immunotherapy the second “trump card”, then tumor vaccines are undoubtedly the third “trump card” of immunotherapy. And it is also what I will introduce to you today: a tumor vaccine called GP2, which has led to a zero five-year recurrence rate in breast cancer patients and can be said to have cured them clinically.

Zero recurrences in the five-year follow-up: the emerging tumor vaccine brings hope of cure

The GP2 vaccine is a nine amino-acid transmembrane peptide derived from the HER2/neu protein. HER2/neu is a cell surface receptor protein, expressed in 75% of breast cancers and other common cancers. And GP2 can train patients’ T cells to recognize and destroy HER2/neu-expressing cancer cells and avoid recurrence.

The related trial enrolled a total of 168 patients, with the primary objective of determining whether the GP2 vaccine could reduce the recurrence rate of breast cancer in combination with the FDA-approved immune adjuvant GM-CSF. The study included patients with operable HER2-positive breast cancer, who were randomized to receive GP2 + GM-CSF and GM-CSF alone after the operation.

According to the study results:

After five years of follow-up, 46 HER2-positive patients who received GP2+GM-CSF treatment had a five-year disease-free survival (DFS) rate of 100% and none had a recurrence, while 50 patients who received GM-CSF treatment had a five-year DFS rate of 89.4% (95% CI: 76.2, 95.5%) (p=0.0338).

GP2 was shown to be well tolerated with no SAEs (serious adverse events) and elicited a potent immune response measured by local skin tests and immunological assays, which suggested peak immunity was reached at six months upon completion of treatment.

In other words, during the five years of trial follow-up, not only did the patients have five years of DFS, but also all of them had no recurrence. Isn’t this the ideal endpoint for all cancer patients? Isn’t this the dawn of cure that all patients are dreaming of?

Besides the major breakthrough in the area of breast cancer, the development of “therapeutic vaccines” for cancers has bloomed all over the world in 2020, with vaccines for various cancers launched. Many hospital medical supply companies have done a lot to this achievement.

Head and neck cancer: the mRNA-4157 vaccine

As an mRNA vaccine developed by Moderna, the mRNA-4157 vaccine uses a novel and gene-based technology, and is designed by comparing patients’ normal cell DNA sequence to that of their tumor, and identifying tumor specific changes to the DNA. By combining with pembrolizumab (a PD-1 inhibitor), researchers hypothesized that the vaccine could prime the immune system to be more responsive to the PD-1 inhibitor and reduce the risk of cancer recurrence.

Moderna announced the ability of mRNA-4157 in combination with Keytruda to shrink multiple advanced solid tumor foci on Nov. 11, 2020.

In 10 patients with HPV-negative head and neck squamous cell carcinoma, the overall response rate (ORR) reached 50%, with two patients achieving a complete response (CR) and three patients achieving a partial response (PR); four patients had stable disease, and the disease control rate (DCR) reached 90%.

The combination had a significant advantage over the use of the PD-1 inhibitor alone: the median progression-free survival (mPFS) reached 9.8 months.

The results were satisfactory even when the combination was compared with the Keytruda / chemo combination (standard of care for first-line treatment), which produced an ORR of 36% and an mPFS of 4.9 months.

This combined immunotherapy has been well tolerated so far, and the investigators plan to expand the study cohort to 40 patients, which means that 40 patients will receive a tailored mRNA vaccine that will stimulate the strongest immune response.

Melanoma: the TLPLDC vaccine achieved a two-year DFS rate of 73%

The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is a personalized treatment that is created using a patient’s own blood and tumor cells. Tumor samples are collected at resection, frozen, and sent to the lab where they are used to create autologous tumor lysate, which is loaded into yeast cell wall particles (YCWP). This combination is then introduced to the patient’s dendritic cells, leading to the creation of the final TLPLDC vaccine. The time from resection to injection of the vaccine takes approximately two weeks.

Results of a subgroup analysis of the Phase IIb clinical trial of the TLPLDC vaccine treating melanoma were presented at the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium.

The study was a prospective, randomized, double-blind, placebo-controlled phase IIb study conducted in patients with resected stage III (advanced) and stage IV (metastatic) melanoma to assess the efficacy and safety of the TLPLDC vaccine.

A total of 144 patients in the study were randomized to receive either the TLPLDC vaccine or placebo to prevent a recurrence. These patients began vaccination within three months of completing the standard of care (SoC) treatment, at 0, 1, 2, 6, 12, and 18 months.

The primary endpoint of the study was 24-month DFS, and the secondary endpoints included DFS at 36 months and overall survival (OS), which were compared between the TLPLDC vaccine group and the placebo group.

Considering the high early recurrence rate among high-risk melanoma patients and the time required for the vaccine’s activation of the immune system, prespecified primary efficacy analyses were performed for both the intent-to-treat (ITT) and per treatment (PT) groups. The PT analysis included all patients who completed the primary TLPLDC or placebo series (PVS) at six months.

In the PT analysis, the 24-month DFS rate was significantly improved in the TLPLDC vaccine group compared to the placebo group (62.9% vs. 34.8%; HR=0.52 [95% CI:0.27-0.98], p<0.041), representing a nearly 50% reduction in the relative risk of disease recurrence.

In the ITT analysis, there was no significant improvement in 24-month DFS in the TLPLDC vaccine group and the placebo group (38.5% vs 27%, p=0.974), however, in this analysis, there was a stronger trend in improved 24-month OS (86.4% vs 75.1%, p=0.15).

Subgroup results

According to the data of the PT analysis, in patients with stage IV melanoma, the 24-month DFS rate was significantly improved in the TLPLDC vaccine group compared to the placebo group (73.0% vs 0), representing a statistically significant and clinically meaningful reduction in the relative risk of disease recurrence in this patient population.

Improvement was also demonstrated in the ITT analysis (43.0% vs 0), showing that stage IV patients were more likely to receive checkpoint inhibitor therapy (50% vs 26%).

Additionally, an initial assessment of 36-month follow-up data on all patients indicated that the TLPLDC vaccine benefit is not only durable but continues to increase beyond 24-months. As a result, the study will continue as designed to the 36-month DFS and OS endpoints.

Besides the above novel vaccines, cancer vaccines have been extensively studied in animal models and humans over the past 30 years, which has involved different types of cancer. Personalized vaccines will be used for different types of cancers because of their potential safety, specificity and good tolerability and safety. It is believed that more and more cancer patients can regain their health with the continuous progress of immunotherapy.

References:

1.Moderna Announces Clinical Updates on Personalized Cancer Vaccine Program. Retrieved November 11, 2020, from https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-clinical-updates-personalized-cancer-vaccine；

2.https://endpts.com/a-cancer-vaccine-that-might-work-moderna-posts-promising-early-snapshot-for-merck-partnered-program-and-raids-bristol-myers-for-a-new-cancer-rd-chief/；

3.Elios Therapeutics Presents Primary Analysis of Phase IIb Study Showing Personalized Cancer Vaccine Significantly Reduces Risk of Melanoma Recurrence in High-Risk Patients.