Personalised Cancer Vaccines

When everything old is new again

The cancer vaccine landscape is marked by two decades of clinical failures. Although sipuleucel-T was approved as a therapeutic vaccine for prostate cancer, the company filed for bankruptcy because of lack of demand for such complex cell-based vaccine. However, tumour neoantigens that are unique to each patient’s tumour are now renewing interest. Several groups have shown that neoantigens are critical for success of checkpoint inhibitors, raising the possibility that neoantigens may make personalised vaccines.

Currently IVAC mutanome, mRNA-based vaccine with 10 neoantigens per vaccine is in phase I clinical trial in melanoma and NEO-PV-01, peptide-based vaccine with 20 peptides per vaccine is in phase I clinical study with nivolumab for melanoma, non-small cell lung cancer (NSCLC) and bladder cancer. ADXS-NEO, bacteria-based vaccine with 20-50 neoantigens per bacterial construct (but multiple constructs can be delivered together) will enter in phase I study in 2017. A virus-based vaccine with 20-50 neoantigens per vaccine is expected to enter in phase I study for NSCLC in 2017.

Besides interest from biotech companies, some large pharmaceutical companies have recently set collaborative agreements with biotechs.

Many of the first cancer vaccines were built to prime the immune system against tumour-associated antigens (TAAs). For example, tecemotide that targets the mucin 1 (MUC1) antigen advanced to phase III, but was discontinued in breast cancer because of safety issues and in NSCLC because of lack of efficacy. Phase II studies in prostate and colorectal cancers are ongoing.

In term of germline antigens, development of a melanoma-associated antigen 3 (MAGEA3) vaccine was discontinued in NSCLC and melanoma because of disappointing clinical data, however, a phase II trial in bladder cancer is ongoing.

Whereas many of the first cancer vaccines trained the immune system to search out the single TAA, the researchers can now prime the immune system against dozens of neoantigens. Although, it remains to be seen whether the use of multiple neoantigens boosts clinical efficacy, it stands to reason that this could help to tackle heterogeneous cancers while also raising the bar against immune escape.

Most mutagenic cancers (e.g. melanoma and lung cancer) can harbour hundreds of neoantigens. Therefore, it’s key which neoantigens to incorporate into personalised cancer vaccine. However, even true neoantigens are identified, the researchers struggle to predict which are likely to be most immunogenic. In that regard, the researchers have developed different computational tools to guide decision.

In term of vaccine delivery platforms, engineered Listeria bacteria can carry up to 50 neoantigens. In viral approach, the antigens are encoded in RNA of a hybrid virus. Different antigen-deliver platforms have strengths and weaknesses to be taken into consideration, but currently it’s unknown which platform will work the best.

The personalised nature of each vaccines offers a plenty of production pitfalls. Although companies currently need 6-12 weeks to generate a personalised cancer vaccine, they are aiming at bringing the production timeline down to one month. If and when cancer vaccines move to earlier stages of disease, when the immune system might be in better shape to take on cancerous tissue, the delay may become less consequential.

EGFRvIII is present in 34-64% of glioblastomas meaning that EGFRvIII vaccine need not manufacture each time anew. However, an interim analysis of a phase III trial in glioblastoma earlier this year suggested that a peptide-based vaccine against that antigen wouldn’t meet the efficacy endpoints.

Despite the lack of success of TAA-based vaccines, some researchers remain committed to such approach reasoning that wrong cancer types have been chosen for research in the past, or that development strategies were committed to late stage, fast progressing cancers.

Furthermore, the researchers think that combination strategies might be successful. Checkpoint inhibitors in particular may work well with both, TAAs and neoantigen vaccines.

Reference

Mullard A. The cancer vaccine resurgence. Nature Reviews Drug Discovery 2016; 15: 663-665.