Cancer Vaccines: Activate the Immunosoldiers – Part II

The Experts
 

In part I of this special feature, we explored why cancer vaccines are causing so much excitement in drug development and exactly how they harness the immune system to destroy tumors. Here, we ask our experts at the challenges that lie ahead – and how we separate the hype from the reality.

What are the biggest lessons learned to date from current cancer vaccine research?
 

Jens Bjørheim: A pivotal lesson learned is the importance of combining vaccines with checkpoint inhibitors. When tumorigenesis begins, the immune system begins to detect that something is wrong. The cancer cells shield themselves by activating immune checkpoints that protect them from being attacked by the immune system. The checkpoint inhibitors remove these shields, enabling the immune system to eliminate tumors across various cancer types.

However, some patients may lack a sufficient T cell repertoire to combat the tumor. In such cases, therapeutic cancer vaccines can introduce new T cells that are specifically designed to target, recognize, and kill the tumor.  

Myriam Mendila: Agreed. We have also learned that vaccines work better in hot (inflamed) tumors. Plus, patients with lower tumor burden or in the earlier stage of disease often derive more benefit from cancer vaccines because their immune system is still functioning well and the tumor volume is smaller.

Nicolas Poirier: Treating early is definitely key. Personalized vaccines are very promising for those diagnosed early and when the tumor is not growing too fast. For advanced and metastatic cancers, identifying patients who have benefited from previous immunotherapy treatment is important to select immune-sensitive tumor types that are more likely to benefit from vaccination.

Paul-Peter Tak: I’d highlight three important learnings. First, identification of single tumor antigens that are shared between patients and that could be used for an off-the-shelf vaccination strategy have proven difficult across various solid tumors. Second, tumor cells may escape the immune response after vaccination against a single tumor antigen. Third, cancers may elude the immune response by producing factors that exhaust tumor infiltrating lymphocytes or inhibit their migration into the tumor.

Justin Duckworth: The resurgence in interest driven by mRNA vaccines has encountered many of the challenges of previous decades. This is unsurprising – because mRNA technology on its own is not a new angle on trying to overcome the inherent problems of cancer vaccination. In mRNA, considerable research effort has been expended in trying to optimize LNP design to influence the adjuvant effect of the vaccines, as well as mRNA design for potent production of the target antigen. 

The area where perhaps most new ground has been broken is in neoepitope discovery. This field aims to customize a cancer vaccine by sampling the individual’s tumor and isolating neoepitopes. mRNA vaccines are well placed to capitalize on advances in this field because they can deliver multiple antigen payloads to prime the immune system.

And what are the big challenges moving forward?
 

MM: A significant challenge is deciding which tumor antigens to target. Some patients have 8,000 tumor-specific antigens; others have just 100 or less. We need to develop smart selection algorithms based on specific criteria, supported by AI, to identify and prioritize the antigens that really matter. 

A second challenge is the ability to deliver vaccines quickly. This can go down two routes – the provision of pre-prepared or so-called “off the shelf” cancer vaccines based on tumor antigens known to be shared across different cancer indications or fully personalized vaccines based on a patient’s individual tumor genomic profile. The former is faster as relevant antigens can be anticipated while the latter takes longer due to mandatory steps, such as taking a biopsy, sequencing the tumor tissue of a given patient, designing and producing an individualized vaccine, and getting the vaccine to the patient. This can take around 6 weeks to 3 months. We need to find solutions to produce the personalized cancer vaccine in particular in the fastest way as patients with cancer usually can’t wait for their treatment.  

NP: In addition, identification of the right antigens is not the same at the early versus late stage – because tumors evolve and resistance mechanisms vary. This means we need to diagnose more patients, especially those with solid tumors, at an earlier stage and to prepare ‘off-the-shelf’ vaccines composed by several shared tumor-associated antigens across tumor development to treat quickly patients and avoid tumor escape from one or two antigen mutations.

JD: Despite considerable effort expended in predicting neoepitopes using AI and machine learning, the current hit rate of predicted neoepitopes remains poor – around 5–10 percent. Significant educated guesses still need to be made because of the sheer number of combinations of MHC class I molecules and nano-peptide extracts of mutated proteins to be sifted through. Boosting this success will improve the specificity of the vaccine effect and, ultimately, create more potent vaccines. Secondly, despite efforts to indirectly program immunity by skewing the response to become more T cell dominant, it remains more art than science with considerable educated guesswork as to how the downstream complexities of antigen presentation and T cell activation play out.

P-PT: Engineering the right agent to engage the immune system in the right way to yield durable antitumor responses is a challenge. Approaches designed to stimulate the anti-tumoral response ex vivo against multiple antigens are elegant, but implementation is complicated by relatively high costs, extended timelines, and its use is limited to specialized centers. mRNA vaccination is simpler in terms of implementation, but provides different challenges because it typically focuses the immune response against a single antigen.

JB: Though checkpoint inhibitors have demonstrated substantial efficacy, they do not work for all patients. In some indications, such as malignant melanoma and non-small cell lung cancer (NSCLC), a higher proportion of patients respond compared with other indications like mesothelioma and head and neck cancer. Additionally, some cancers, such as prostate and pancreatic cancers, have yet to establish checkpoint inhibitors as standard of care.

Because of the mutual interaction between checkpoint inhibitors on one side and the immune system or vaccines on the other, patients who do not respond to checkpoint inhibitors are likely to see little or no effect from a therapeutic cancer vaccine. To broaden the application of vaccines, we need new checkpoint inhibitors or drugs that make the tumor more accessible for the immune system.

What is the future of cancer vaccines, and how do we separate hype from reality?
 

MM: Based on data with other immunotherapies in cancer, such as checkpoint inhibitors, we see that targeting the immune system may be the best or even only way to achieve a real cancer cure. It makes sense to combine different immune therapies with cancer vaccines to increase the chance of success in curing cancer and the recent data support the current hype around cancer vaccines. To separate this hype from reality, we need to be very rigorous in the way we conduct clinical trials, how we interpret the data, and how we make decisions based on data.

P-PT: Approaches resulting in vaccination against the patient’s tumor represent a new frontier in cancer research. The difference compared with conventional immunotherapies is that a vaccination strategy may help to educate the patient’s immune system how to recognize the tumor cells in a specific way, which could lead to durable clinical responses and improved survival with a superior quality of life. We will separate hype from reality by evaluating the benefit/risk of specific new vaccination strategies in patients with cancer.

NP: Large phase III randomized trials in early/adjuvant settings as well as advanced cancer patients are required to confirm the benefit of cancer vaccines for patients in terms of efficacy, better safety, and preserved quality of life compared with chemotherapy. Then, cancer vaccines can become part of the therapeutic arsenal in the quest for a cure for cancer.

JB: I believe that therapeutic cancer vaccines are poised to become an established standard of care in several different tumor types, most likely when combined with checkpoint inhibitors. There is opportunity for several different modalities, such as RND, DNA, and peptide vaccines, as well as strategies ranging from personalized vaccines to more generalized vaccination approaches. Moving forward, the issues of cost and access in terms of affordability and patient accessibility will be increasingly important. 

JD: New cancer therapies are mostly incremental to the standard of care and vaccines will find their place, most likely, in patients with minimal signs of being immunocompromised. The apparent safety and cost profile of the most recent mRNA cancer vaccines suggests even modest clinical success will be rapidly adopted. Increasing understanding of tumor biology combined with new technologies will help drive us to an inflection point.

The dramatic success of COVID-19 vaccination has inevitably driven a degree of hype, and mRNA vaccine companies are now revisiting cancer vaccines following their successful incursion into infectious disease. However, to those knowledgeable in the field, there is a strong understanding of the difference between success in a prophylactic setting with a known antigen, versus that in a therapeutic setting with individualized neoantigens. Hype is actually a rare beast in this field as cancer vaccines have endured decades of promise that has underdelivered, resulting in a permanent state of healthy skepticism from the investment community. 

Ultimately, the only cure for hype is convincing clinical data, something the field may be moving closer to regularly achieving.