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20 BioPharm International ® Emerging Therapies eBook September 2023 www.biopharminternational.com Vaccines vaccine against infectious pathogens. Conventional vaccines can directly provoke a targeted immune re- sponse in essentially the same way that an infection does: by exposing the immune system to a dead or weakened pathogen, or its parts. Exposing the im- mune system to a less-threatening form of a harmful pathogen is sufficient for the adaptive immune sys- tem to learn how to target the pathogen and repeat the targeted response if the pathogen is encountered in the future. Regardless, the "less threatening" form of a cancer cell is a healthy cell. So, in the case of cancer vaccine development, the options for provoking a targeted immune response are much more constrained. A can- cer vaccine must trigger an immune response against cancer without provoking autoimmune-mediated damage to healthy cells and tissues, meaning that the antigen, or the molecule specifically targeted by the immune system, must be cancer specific. Traditional vaccination methods are not able to achieve this level of antigen specificity. A personalized approach Of the vaccination methods, an mRNA-based vaccine has been widely considered the most promising for cancer because it can be sufficiently precise. Unlike conventiona l vaccines t hat provoke t he immune response directly, an mRNA vaccine on ly carries instructions that provoke the immune system in- directly (3). The mRNA instructions are "read" by healthy cells, which temporarily produce a foreign protein encoded by the mRNA. The production of foreign proteins by healthy cells then triggers a tar- geted immune response. This method can also be used to instruct cells to produce proteins that ar- en't from pathogens—including proteins expressed only by cancer cells. However, until recently, identif ying appropriate cancer antigen candidates has been a major road- block for cancer vaccine development. Many antigens commonly overexpressed in cancer are also expressed by hea lt hy cel ls. Ot her ca ncer-speci f ic a nt igens are the result of unique tumor mutations that vary between individuals (4). Presently, the most promising cancer mRNA vac- cine candidates are personalized to take advantage of the unique proteins that arise from tumor muta- tions (neoantigens). Moderna's personalized mRNA vaccine (mRNA-4157), which received breakthrough therapy designation for the treatment of melanoma, primes the immune response against 34 of these pro- teins at once (1). Combination therapies However, even precisely targeted vaccines may not be effective on their own. Cancers that have survived long enough to endanger a patient's health have generally developed ways to resist or evade a targeted immune response, often by co-opting mechanisms that help pre- vent autoimmune damage, such as an immune check- point (5). Consequently, mRNA cancer vaccines that are currently in development are administered in combi- nation with another therapy that can help counteract immune evasion or suppression by cancer. For example, Moderna's mRNA vaccine (mRNA- 4157) is administered in combination with an immune checkpoint inhibitor (ICI), which helps immune cells that target cancer, called T cells, endure the tumor microenvironment. In a Phase IIb trial, this combina- tion proved more successful than treatment with the ICI alone. After one year, 157 patients treated with the combination therapy had a 44% reduced risk of cancer recurrence or death (1). Promising Phase I results, demonstrating strong T-cell responses, were also reported in June 2022 by BioNTech for a similarly personalized method of mRNA vaccina- tion (BNT111) for patients with advanced melanoma. The vaccine, which targets the antigens NY-ESO-1, MAGE-A3, tyrosinase and TPTE, was administered in combination with an immune checkpoint inhibitor and chemother- apy (6). BNT111 received FDA Fast Track designation in November 2021. Another approach, which has demonstrated early clinical promise, is an mRNA vaccine that enhances the proliferation of T cells genetically engineered to target cancer (chimeric antigen receptor [CAR] T cells). A Sep- tember 2022 Phase I/IIa trial of a CLDN6-directed CAR T-cell therapy, in combination with an mRNA vaccine for the CLDN6 antigen, displayed one of the first examples of CAR T-cell efficacy in solid tumors, with 43% of pa- tients treated with the combination therapy exhibiting tumor shrinkage (6). Logistical considerations for clinical development While evidence of efficacious mRNA vaccines for cancer accumulates, logistical challenges in cancer vaccine clinical development remain. Many of the considerations for personalized mRNA cancer vac- cines are shared by other cell and gene therapies (CGTs), such as CAR T-cell therapy, where challenges with complexity and cost have limited scalability and inf lated the costs of approved therapeutics. In turn, many of the learnings gained from developing CGTs are relevant to mRNA vaccine development, includ- ing in patient recruitment, manufacturing, regula- tory compliance, and funding. Patient recruitment The eligible population for mRNA-based cancer vac- cines may include patients with solid tumors early in their disease course and is likely to be much larger than approved CGTs that primarily target rare diseases