“If I Can See It, I Can Kill It”

If one could use the word “elegant” to describe anticancer therapy, that moniker would apply to messenger RNA (mRNA) vaccines.

The elegance of mRNA vaccines derives from their apparent ability to overcome one of the major limitations of conventional cancer vaccines: HLA restriction. Most cancer vaccines are composed of glycoproteins that only fit inside the antigen-presenting pockets in human leucocyte antigen (HLA) molecules – our cellular “home address” – a certain percentage of the time. Consequently, anyone treated with a protein-based vaccine is fortunate to achieve an immune response.

By contrast, an mRNA vaccine can code for as many as 34 “neoantigens” based on the DNA of a patient’s tumor. Several of these neoantigens will fit within the HLA pocket, where they enable antigen recognition by the patient’s T cells, leading to elimination of the tumor cells.

mRNA vaccines have crossed two key thresholds: (1) improved effectiveness, compared to most other cancer vaccines; and (2) broader applicability, with potential benefits accruing to greater numbers of patients. The vaccines work synergistically with checkpoint inhibitors because of the capability of mutated proteins in cancer cells to induce expression of programmed death ligand 1 (PD-L1) and other immune checkpoints on the cell surface. If a protein is presented by an HLA mutation in the major histocompatibility complex (MHC) pocket, and binds that antigen to a T-cell in an HLA-restricted manner, it allows the T-cell to grow and expand against that specific protein. Upon recognizing the mutated protein, PD-L1 engages the programmed death receptor on the T-cell, thereby turning off the T cell.[1]

Checkpoint inhibitors essentially act to keep the T-cell “light switch” on, preventing PD-L1 from engaging the receptor. The problem is that certain cellular processes turn the switch off, in much the same way as someone might inadvertently turn off a light by bumping into a switch on a wall. Only about half of the neoantigens produced by translation of mutated DNA fit inside the MHC pocket for presentation on the cell surface, where the T-cell is turned “on” and will recognize a neoantigen-expressing cancer cell as something it must kill. To keep the T cell kill switch on, the checkpoint inhibitor blocks the “off” switch.[2]

mRNA vaccines facilitate this process by increasing the translation of mutated proteins so enough of the neoantigens fit inside the MHC pocket for presentation to the T cells. By enhancing antigen presentation and keeping the T-cells turned on, the mRNA vaccine/checkpoint inhibitor combination enables better and more robust T-cell recognition of the mutated proteins on the cell surface, allowing the T-cells to kill more cancer cells more rapidly.

mRNA vaccines are developed from sequencing a person’s cancer cell DNA and pattern-matching it to the person’s “normal” DNA, to see where mutations occurred. That allows scientists to create mRNA only from mutated DNA and to encapsulate the mRNA in a lipid nanoparticle that is administered to the patient via injection. The mRNA enters antigen-presenting cells (APCs, consisting of macrophages and dendritic cells) to be translated into neoantigens to mount a massive immune response against the cancer cells.

As an immunologist, I find the mechanism of mRNA vaccines so exciting it gives me goosebumps. That we can sequence normal DNA as well as tumor DNA, pattern-match both sets of DNA to identify mutations, create-mutation specific mRNA, wrap the mRNA in a liposome, infuse it within 20 days of harvesting a patient’s cells, and administer it with a checkpoint inhibitor to achieve substantial effectiveness without inducing more immunotoxicity, is remarkable.

I saw these effects first-hand when our cancer center was one of several institutions that participated in a recent study in patients with melanoma, in which combining an mRNA vaccine with pembrolizumab reduced the disease recurrence rate by almost half, compared to pembrolizumab (Keytruda®; Merck & Co) alone. [3]

Marshaling the forces to eradicate cancer
The advent of mRNA vaccine therapy is a paradigm-shifting development in that it opens the door to enhancing current immunotherapeutic approaches. The promise of these powerful agents lies in their potential to engender effective immune responses via basic mechanisms. An mRNA vaccine stimulates T-cell recognition of multiple foreign proteins and mobilizes an army of T-cells to kill any expression of those proteins; this process is already available to us, and it is nothing short of a breakthrough.

The next breakthroughs will involve the use of cytokines, novel checkpoint inhibitors, and modified MHC molecules to completely eradicate cancer cells in all patients, as opposed to working only in selected individuals, as checkpoint inhibitors currently do. Although this latter capability is not yet available, recent advances suggest its arrival is not too distant. But for any mechanism to work, the T-cell must recognize the cancer cell as foreign. In other words, the T-cell cannot kill what it does not see.

As excited as I am about the reduced recurrence rate in our recent melanoma study, it is possible to envision even lower recurrence rates in the future. However, attaining such momentous outcomes will require further advances. If an mRNA vaccine can code all 34 neoantigens but none of them fit in the MHC pocket, the T-cells won’t be able to recognize them. Fortunately, researchers are working on developing “user-friendly” MHC pockets designed to facilitate T-cell recognition and binding to any antigen. Such a development may make mRNA vaccines the all-seeing cancer-killers we will need as immunotherapy continues to evolve.

Highlights of prescribing Information
Pembrolizumab (Keytruda®; Merck & Co) [Prescribing Information]

Reference
[1] Falk K, Rötzschke O, Stevanovic S, Jung G, Rammensee HG. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature. 1991;351(6324):290-296.
[2] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264
[3] Sullivan RJ, Carlino M, Weber JS, et al. mRNA-4157 (V940), a personalized cancer vaccine, in combination with pembrolizumab, demonstrates trend for improved recurrence-free survival compared to pembrolizumab alone in adjuvant melanoma patients across tumor mutational burden subgroups. Presented at Association for Advancement of Cancer Research (AACR) annual meeting, April 14-19, 2023, Orlando, FL. Abstract CT224.

Featured image Photo by Braňo on Unsplash. Used with Permission.