In this post, we continue our report on some of the precision medicine approaches and initiatives we noted at ASCO.
Neoantigens Revitalizing Cancer Vaccine Efforts
Early efforts to create cancer vaccines aimed at increasing the immune system’s exposure to tumors, but the effectiveness of first-generation vaccines created by Dendreon and others was limited. Now, several personalized cancer vaccines based on neoantigens are showing potential in early stage clinical trials.
Neoantigens are antigens based on mutated cancer genes that are unique to a patient’s tumor and rarely shared between patients. Recent progress in the next-generation gene sequencing field is enabling scientists to find relevant mutations carried by the patient’s biopsied tumor and incorporate them into personalized cancer vaccines. Such vaccines can then be administered as adjuvant therapy, alone or in combination with checkpoint inhibitors, to direct the immune system against the tumor.
A number of companies are pursuing this approach to personalized cancer vaccines. At ASCO, Genocea Biosciences presented early data from the first five patients of its ongoing Phase 1/2a trial of GEN-009 in melanoma and a variety of solid tumors. They reported that GEN-009 monotherapy elicited specific T-cell responses to 91% of the administered vaccine neoantigens, and it was uniquely able to elicit ex-vivo CD8+ T cell responses, observed for 47% of the vaccine neoantigens. GEN-009 has been well tolerated to date, with no dose-limiting toxicities. Moderna, Inc., Neon Therapeutics, and BioNTech also reported positive early results with their neoadjuvant cancer vaccines, showing the ability of the personalized vaccines to elicit T cell responses specifically directed to the selected cancer mutations.
Neoantigen cancer vaccines offer the benefits of a highly individualized patient approach, as well as opportunities to minimize off-target toxicities. However, several challenges remain to their use, including the ability to find and biopsy sufficient amounts of a patient’s tumor to allow appropriate sequencing, the necessity to find a strategy to handle tumor heterogeneity and genetic evolution over time, the time necessary to design such a vaccine (4-12 weeks), and finally the cost of such approaches.
Potential of Liquid Biopsy to Direct Treatment, Predict Outcomes
We recently wrote on some of the recent advances in liquid biopsy, including new data reported at ASCO on technologies from Guardant Health, Foundation Medicine, and Grail. Several other studies from academic researchers at NYU Langone Health and Northwestern University focused on the benefits of monitoring circulating tumor DNA (ctDNA) throughout the treatment journey as a way of predicting outcomes and pinpointing patients who might require closer follow-up or who could benefit from alternative targeted interventions.
In the NYU Langone Health study, researchers found that continuous monitoring of ctDNA during treatment of unresectable or metastatic melanoma could help identify patients most likely to benefit from Novartis’ drug Tafinlar (dabrafenib), either alone or in combination with Mekinist (trametinib). The 345 patients in the study underwent BRAF V6600E/V600K ctDNA measurements at baseline and week 4. Most of the patients (92.7%) had detectable ctDNA at baseline and nearly all experienced a decrease in ctDNA by the fourth week of therapy. Of the 224 patients who completed the four week ctDNA measurements, 128 remained positive for ctDNA and 96 were negative. Those who remained ctDNA positive, had a significantly shorter median progression-free survival (7.4 months versus 13 months) and overall survival (15.3 months vs 27.9 months) than patients who became ctDNA-negative.
The first of two studies at Northwestern University explored the role of circulating tumor cells (CTC) and ctDNA to predict sites of metastases in 85 patients with metastatic breast cancer (MBC). The researchers found that ESRI mutations were strongly associated with liver metastases in hormone receptor negative (HR-) patients and bone metastases in HR+ patients; in addition, patients with high CTC counts were also more likely to develop bone metastases. The researchers suggested that evaluation of ESRI mutational status and CTC count level could help pinpoint patients who should be considered for alternative treatment options and be more closely monitored via imaging.
In the second Northwestern study, conducted in the same patient group, the researchers analyzed CTCs and cell-free DNA (cfDNA) to investigate the impact of biological tumor characteristics on disease prognosis. They found that patients whose cfDNA had ESRI mutations and HER-2 alterations had a higher number of CTCs and a higher average number of metastases than patients without ESRI and HER-2 mutations. Patients with both mutations in ESRI and alterations in HER-2 also had worse overall survival than those without the mutations. While the investigators noted their findings were preliminary, they hoped further studies could show that the combination of mutations resulted in more aggressive disease, which could help physicians monitor disease progress and help guide treatment.