Daina Vanags, PhD- Principal Consultant and Senior Director; Cori Gorman, PhD- Senior Director, Biopharmaceutical CMC and Regulatory Affairs; Christian K Schneider, PhD- Head of Biopharma Excellence and Chief Medical Officer, Biopharma Excellence
Cancer research has come a long way in a short space of time. As immunotherapy and gene therapy pioneer Dr. Stephen Rosenberg has pointed out, the traditional tools available to treat cancer - surgery, chemotherapy and radiotherapy – now have a fourth pillar: immunotherapy.1
Advances in immunotherapy treatments, starting with early steps such as Interleukin-2, and more recently the US-FDA approved immunotherapies that target critical immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death receptor 1 (PD-1) represent significant advances and are now standard of care treatments for advanced melanoma.2 More recently, genetically engineered T cells or chimeric antibody receptor (CAR)-specific T cell therapies, which utilize known tumor-associated antigens to attract tumor-specific T cells into the tumors, have dramatically improved outcomes for many cancer patients.3
An important next step in the journey is the development of cancer vaccines. There has been huge success with vaccination against human papillomavirus (HPV), following evidence that 95% of cervical cancers are due to HPV4 - specifically HPV types 16 and 18 and further findings that HPV is likely to be responsible for 70% of oropharyngeal cancer.
Although the HPV vaccines do not clear existing HPV infections, the success of the HPV vaccines has established the principle that cancer can be prevented, perhaps even treated, by a vaccination.
Eradicating Cancer Cells
Current research sets out the potential for therapeutic vaccines to treat patients with cancer with the hope of eradicating cancer cells – and not just those caused by viruses. Areas in which promising research into therapeutic vaccines is taking place includes vaccines to induce an immune response against E6 and E7 oncoproteins in advanced cancers of the head and neck.5 E6 and E7 are the main oncoproteins in high-risk HPV types.
Another area with potential is peptide-based specific, sometimes individualized, tumor vaccines. Advances in high-throughput genomic analysis as well as in epitope prediction “have enabled the design of personalized epitope peptides on the basis of mutations in cancer.”6
A third area that has shown promise is cell-based vaccines with dendritic cells. In fact, one therapeutic cancer vaccine that has received regulatory approval is a dendritic cell-based vaccine (Sipuleucel-T) for castration-resistant prostate cancer, which the US FDA approved in 2010. The vaccine stimulates immune cells with an antigen – in this case prostatic acid phosphatase (PAP) – and an immune stimulant (GM-CSF). The product was withdrawn from the EU in 2015 for commercial reasons and, according to reports, there has been limited uptake of Sipuleucel-T in the clinic.7 Although dendritic cell vaccines have not shown good clinical response since then, improved methods are being researched.
In addition, a comprehensive search of ClinicalTrials.gov shows there is a wealth of research in the field with hundreds of products in various stages of clinical research across many different cancers.
Hot Versus Cold Tumors
Nevertheless, many companies have hit barriers in their attempts to develop targeted therapeutic cancer vaccines.
The first, as with immunotherapy, is the issue of hot versus cold tumors. Cold tumors are less immunogenic, while hot tumors are immunogenic, with an abundance of immune cells present, and T cells can be activated to attack tumor antigens. There are a number of strategies to turn cold tumors into hot tumors to make them more sensitive to immunotherapy. Cold, or non-inflamed tumors, are generally characterized as having a lack of CD8+ T lymphocytes, an abundance of the immunosuppressive cell populations such as tumor-associated macrophages, T-regulatory cells and myeloid-derived suppressor cells, a low mutational load, low major histocompatibility complex (MHC) class I and low PD-L1 expression.
These create an immunosuppressive microenvironment around the tumor, which is then able to evade immune surveillance. Inflamed or hot tumors are characterized by high CD8+ T cell density, which are functionally active and increased tumor PD-L1 expression.
The conundrum is that for a vaccine to work, it has to break down the body’s natural tolerance of the immune system against “self” structures as they are found in tumors, and that can trigger autoimmunity. This would occur either by forcing an immune response against tumor antigens which show similarity with the body’s own structures, or by activating other T cells as well in the drive to overcome immune system silencing, thus activating autoimmune T cells which are usually dormant.
A solution to some of the autoimmunity issues facing cancer vaccines has perhaps been found in the use of neoantigens, which due to their underlying mutations can signal the immune system to target cancer cells without seriously harming non-cancerous cells.
There is also a need to consider tumor progression. Before a patient is enrolled for chemotherapy, the tumor is measured, and treatment is then applied with the objective of shrinking the tumor. If the tumor returns and grows beyond a certain diameter, it is referred to as progression.
With vaccines, however, there is typically a delayed response during which time the tumor might continue to grow. There would therefore have to be a conscious decision to give the vaccine time to work.
Balancing Risk and Potential
The other issue is pseudoprogression, where the tumor size appears to increase as the immune cells infiltrate the tumor before it shrinks – assuming the treatment works as intended. Any study needs to consider this to allow the cancer vaccine treatment time to be effective, while balancing the potential need to start a different treatment regimen.
In many instances, for cancer vaccines to work effectively, and to be shown to work effectively, they need to be tested on patients with intact immune systems. Patients who have had previous rounds of chemotherapy treatment may not be suitable candidates.
Another consideration is that if the vaccine does not work for certain patients, those individuals are potentially being exposed to risk. On the other hand, if patients who have exhausted other options and now have compromised immune systems are treated with the vaccine, there is a very real risk that the data will fail to show efficacy.
With these risks in mind, if such vaccines are considered as an add-on therapy with conventional therapy, it will require a trial design that delineates the add-on effect from that of conventional therapy. Equally, where a vaccine trial is used as an initial therapy, it is important to include criteria to state that, after a certain time, if there is confirmed progression, those patients would be changed to other treatments.
mRNA Gamechanger
Apart from CAR T cells, possibly the biggest recent gamechanger in cancer vaccine research is the mRNA platform, thanks to its potency, specificity, adaptability, safety, and the fact that it can be scaled up quickly for extensive and relatively low-cost manufacturing.8
Indeed, the success of the COVID-19 vaccines can be attributed to many years of mRNA cancer vaccine research, which demonstrated the safety and low side-effect profile of mRNA vaccines. From a regulatory perspective, the success of the COVID-19 vaccines perhaps instils a level of trust in the technology and is seen as a proof of concept, which will be key to overcoming some hurdles for cancer vaccines during the regulatory submission process.
Novel technologies, such as next-generation sequencing optimization using artificial intelligence, paired with scientific advances in areas such as mRNA or altered peptide ligands with powerful immunoactivators may be the key to cancer vaccine innovation.9
AI has already played a major role in the development of peptide vaccines against RNA viruses, aiding in the prediction of components that generate an immune response, tracking the structure of viruses, and assessing the value and potential of a vaccine. Consequently, its potential for cancer vaccine research cannot be underestimated. With that being said, a lot of progress still needs to be made for cancer vaccines to be effective, and it will take a combination of laboratory research and digital technologies, like AI-based algorithms, to predict early-stage diseases, working alongside regulatory authorities to make therapeutic cancer vaccines a reality.
References
1. The development of cancer immunotherapy and its promise for treating advanced cancers, September 2021. https://www.youtube.com/watch?v=pVMl0LgdnOU
2. Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/− Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets, Gide, T.N. et al, Cancers, May 2021. https://www.mdpi.com/2072-6694/13/13/3186
3. Gene-engineered T cells for cancer therapy, Kershaw, M.H. et al, Nature, July 2013. https://www.nature.com/articles/nrc3565
4. Cervical cancer, WHO, February 2022, https://www.who.int/news-room/fact-sheets/ detail/cervical-cancer#:~:text=HPV%20and%20cervical%20cancer,the%20human%20 papillomavirus%20(HPV).
5. Therapeutic Vaccines for HPV-Associated Oropharyngeal and Cervical Cancer: The Next De-Intensification Strategy?, Morand, G.B., et al, International Journal of Molecular Studies, July 2022. https://www.mdpi.com/1422-0067/23/15/8395
6. Peptide vaccine-treated, long-term surviving cancer patients harbor self-renewing tumor specific CD8+ T cells, Mizukoshi, E., et al, Nature, June 2022, https://www.nature.com/articles/s41467-022-30861-z
7. Moving on From Sipuleucel-T: New Dendritic Cell Vaccine Strategies for Prostate Cancer, Sutherland, S., et al, Frontiers in Immunology, March 2021. https://www.frontiersin.org/articles/10.3389/fimmu.2021.641307/full
8. mRNA vaccines for cancer immunotherapy, Vishweshwaraiah, Y.L., and Dokholyan, N.V., Frontiers in Immunology, December 2022. https://www.frontiersin.org/articles/10.3389/fimmu.2022.1029069/full
9. Personalized therapy with peptide-based neoantigen vaccine (EVX-01) including a novel adjuvant, CAF®09b, in patients with metastatic melanoma , Mørk, S.K., et al., Oncoimmunology, Jan 2022, https://pubmed.ncbi.nlm.nih.gov/35036074/
Daina Vanags, Ph.D., is a principal consultant and senior director with Biopharma Excellence. [email protected]
Cori Gorman, Ph.D., is Senior Director, Biopharmaceutical CMC and Regulatory Affairs at Biopharma Excellence. [email protected]
Christian K Schneider, M.D., is Head of Biopharma Excellence and Chief Medical Officer of Biopharma Excellence. Biopharma Excellence is a PharmaLex company. [email protected]
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