Personalized Cancer Vaccine Development

Although immunotherapy has recently revolutionized many cancer treatments, the concept of an effective personalized cancer vaccine has been in the making for decades. Today, strides in the efficacy of such treatments have produced a number of experimental vaccines in a variety of platforms.

Provisionally successful outcomes in mice and human clinical trials have demonstrated the potential viability of tailor-made vaccines using a patient’s own cancer cells. Just as no two people are alike, neither are their cancer cells, nor are those cells’ number and unique genetic mutations. As understanding of how to identify tumor-specific mutations that enable successful targeting of T-cell responses continues to grow, personalized cancer vaccines may one day be within reach.

Research is hoping to stimulate the immune system to effectively target tumor-specific proteins, or neoantigens, via cytotoxic CD8+ T cells supported by CD4+ T cells. Some believe that neoantigen-specific personalized cancer vaccines may be advantageous compared to tumor-associated antigen therapies due to their ability to trigger specific T-cell responses against abnormal or mutated cells, thereby lessening the risk of damage to healthy cells. Neoantigens also have the potential to prompt immunological memory, which may improve long-term protection against tumor reoccurrence.¹

The higher the number of tumor mutations, the greater the number of possible neoantigen vaccine candidates. That’s good news. However, those cell mutations must be weighed against the type of mutations and to what extent they are expressed. For example, a study of patients with pancreatic cancer showed that although overall survival was not affected by neoantigen load, the quality of neoantigens did have a positive effect. Additionally, this same study also found that survival rates were positively affected by the combination of neoantigen load and diversity of CD8+ T cells. The ability of T cells to specifically target tumors and the potential of Treg cell-mediated vaccine suppression must all be considered as studies continue.²

Vaccine Considerations

Early clinical trials of neoantigen-based cancer vaccines were conducted primarily postsurgery when no additional treatments were indicated. Today, however, researchers are considering not only the types of tumors against which a personalized vaccine might be more effective, but whether a vaccine would be most effective when administered in the earlier stages of tumor activity when the immune system is more robust, or later postsurgery and in conjunction with immunotherapy when a greater number of available antigens might enable a multipronged approach.

Additional lines of research are considering whether personalized cancer vaccines would be most effective in combination with immune checkpoint inhibitors for an enhanced immune response, particularly in cancers with a lower number of mutations and fewer neoantigens. Indeed, numerous viable candidates exist for a personalized cancer vaccine approach.

For a personalized cancer vaccine to be efficacious, it must be produced quickly and be cost-effective. The time necessary to manufacture the vaccine will be dependent on the vaccine platform and drive treatment decisions toward those with the greatest chance for success. It is also possible that starting the patient on adjuvant treatment postbiopsy while the vaccine is in development could provide additional benefit in conjunction with the vaccine itself.

Tumor Cell Identification and Targeting

To identify target cancer cell mutations, whole exome sequencing of a biopsied tumor and surrounding nonmalignant cells is performed to compare the tumor and DNA. RNA sequencing can further identify the type of mutation, although some mutations may not result in recognized neoepitopes, which would necessitate prediction through human leukocyte antigen (HLA) typing.²

In theory, once vaccinated, a robust immune response should kick in as the uptake antigens prompt lymph node draining. As antigen-specific T cells grow, cancerous tumors expressed in neoantigens are targeted and killed, leaving only the memory T cells, central (TCM), effector (TEM), resident (TRM) and peripheral memory (TPM), a subset of CD8+ T cells. It is hoped that these memory T cells may be able to help to prevent future cancer reoccurrences by quickly responding to new antigen threats.

While there are numerous lines of study in the field of personalized cancer vaccines, three in particular are showing promise: those using messenger RNA (mRNA), DNA and tumor antigen peptides.

mRNA Vaccines

After 30 years of research into the deliverability of stable forms of mRNA-based vaccinations, excitement of mRNA as a possible cancer vaccine is growing thanks to the success of the COVID-19 vaccine.3 mRNA vaccines are being evaluated in multiple clinical trials on a variety of cancer types.

Once tumor cell mutations are identified, algorithms can be used to predict which neoantigens are most likely to bind with T cells. Functionally, mRNA is taken up by dendritic cells, which, via nucleotides, instruct the manufacturing and sequencing of spike proteins that will deliver antigens to T cells. The T cells are then able to use this information to recognize the foreign invaders and trigger production of protective antibodies specific to the molecular features of the cancer cells.³

But, determining how to effectively deliver an mRNA vaccine has been a challenge since it is less stable than, for instance, a DNA-based vaccine that requires special storage and handling. One solution may be to encase mRNA inside lipid nanoparticles. This seems to function as a protector of the mRNA, making it invisible to the immune system and thereby potentially enhancing the vaccine’s effectiveness.

However, despite the limited success of mRNA vaccines to date, multiple clinical trials are underway looking for new opportunities to increase their effectiveness. One such trial uses a mRNA cancer vaccine in conjunction with a PD-1 inhibitor. This particular trial is moving onto Phase III after a Phase IIb trial showed a reduction in tumor reoccurrence by 44 percent in stage III and stage IV melanoma patients postsurgery.¹

Another study showed provisional success delivering mRNA vaccines to melanoma patients with T-cell response developed against multiple neoepitopes, with most patients remaining disease-free for 26 months posttreatment. One patient who relapsed received an anti-PD-1 antibody combination therapy and was again determined to be disease-free.⁴

DNA Vaccines

There are more than 200 trials evaluating the efficacy of DNA as a viable personalized cancer vaccine alternative. DNA vaccines are stable, with no need for strict cold-chain requirements.⁴ They can be engineered to include multiple neoantigens; be combined with immunotherapies and immune modulators; and possibly lower the risk of side effects such as damage to healthy tissues and vaccine intolerance that are sometimes seen in patients who receive an mRNA vaccine.⁶

DNA vaccines can be optimized, including amino acid sequencing and lengthening of neoantigen fragments, so that they can be introduced into the tumor in a precise format that maximizes an immune response. Longer epitopes seem to prompt a lengthier immune response and thus increased immune system recognition. However, immune modulators such as anti-PD-L1 checkpoint blockades would likely be needed to boost their chance of success.⁶

DNA vaccines targeting breast cancer studied in mice at the Washington University School of Medicine in St. Louis have demonstrated they can prompt an immune response that effectively shrinks tumors. However, a human study conducted on a single patient with pancreatic cancer showed no change in tumor size even though a measurable immune response was noted.⁶

Although neither DNA nor RNA vaccines as yet have shown significant clinical benefit, research marches on in hopes of finding a possible viable personalized cancer vaccine using one of these modalities.⁶

Tumor Antigen Peptide Vaccines

Long peptide-based vaccines are being studied in a variety of cancers, albeit also with mixed results. In a small Phase I study, NeoVax (with 20 different long peptides) was administered to patients with stage III and stage IV melanoma postsurgery, along with CD4+ and CD8+ T cells. After 25 months, the stage III patients remained disease-free; however, the stage IV patient saw reoccurrence within a few months. After treatment with an anti-PD 1 antibody, T-cell response was broadened, and the tumor showed signs of regression. A second slightly larger Phase I study combined mRNA-encoded melanoma antigens and personalized neoantigen peptides resulting in CD8+ T cells that was comprised of both central memory (TCM) and effector memory (TEM) cells, as well as CD4+ T cells, in even greater numbers.²

Conversely, two studies in patients with glioblastoma, a cancer with a typically low mutational burden, showed no clear benefits attributed to peptide-based vaccines. Both studies did, however, demonstrate the potential of neoantigen-based vaccines to stimulate T-cell response on tumors with low mutational burdens, warranting further study.²

Cost and Benefit

The costs associated with development, including clinical trials, of a personalized cancer vaccine is prohibitive, a fact that further complicates the already immense challenge of identifying viable options.

Researchers at Mount Sinai are looking to develop cancer vaccines based on common mutations seen across many patients, and testing a shared neoantigen vaccine for myeloproliferative neoplasms that allows for the development of vaccine peptides that target a calreticulin gene mutation that affects nearly one-third of patients.⁷

As researchers continue to study how personalized cancer vaccines may best activate T-cell response, particularly CD8+T, the addition of complementary therapies may be a strong treatment component. To date, clinical trials of personalized vaccines in conjunction with immune-checkpoint inhibitors have demonstrated only modest improvements over immune-checkpoint inhibitor monotherapy alone. Testing of personalized vaccines in combination with PD-1 or PD-L1 inhibition and CTLA4 inhibitors may be a logical next step to explore the possibility of an anti-PD-1-mediated response using a combination therapy.²

Vaccine Boosters

Whatever personalized approach is taken, there is a high likelihood that patients will need additional booster vaccines so that T-cell memory can be continually stimulated, particularly given the gradual challenge of T-cell exhaustion. Timing of booster vaccines should be considered in conjunction with any other treatments for a maximal therapeutic approach. In the case of a reoccurrence, DNA sequencing may offer an assessment of T cells and alternative neoantigens, as well as possible information as to why the vaccine did not perform as hoped, all of which would inform future treatments.²

As research into personalized cancer vaccines continues, optimizing delivery routes and timing in combination with any supportive immunotherapies will drive future success.