The concept of using vaccination to eradicate cancer by instructing the immune system to eliminate malignant cells has been pursued for decades with little success. Stimulating an immune response against cancer is more complicated than immunizing the body against an infectious agent: To be successful, cancer vaccine approaches must overcome significant hurdles, including low immunogenicity and the immunosuppressive effects of the tumor microenvironment. & nbsp,
So far, only a few therapeutic vaccine products have received approval by the U. S. Food and Drug Administration. These include sipuleucel – T( Provenge ), a cell – based vaccine approved as a therapy for advanced prostate cancer, talimogene laherparepvec ( T – VEC or Imlygic ), an oncolytic virus vaccine approved for the treatment of metastatic melanoma, and Bacillus Calmette – Guérin, a live attenuated bacterial strain used to prevent early – stage bladder cancer from coming back after surgery. & nbsp,
Other vaccines have shown promise in preclinical studies but had very limited success in demonstrating clinical benefit. & nbsp,
Recently, some vaccine approaches have made headway, leading to optimism that effective therapeutic cancer vaccines may now be within reach. What has changed, and how are newer cancer vaccines getting closer to making a difference for patients? & nbsp, & nbsp,
Data discussed at the AACR Annual Meeting 2023 may help answer these questions. & nbsp,
Selecting More Effective Vaccine Targets & nbsp, & nbsp,
” Past vaccine strategies over the last 25 years attempted to induce immune responses against so – called tumor – associated antigens, which are not absolutely specific to the tumor as opposed to any normal tissue”, said Jeffrey Weber, MD, PhD, deputy director of the NYU Langone Perlmutter Cancer Center and Laura and Isaac Perlmutter Professor of Oncology at NYU Grossman School of Medicine. & nbsp,
Tumor – associated antigens are proteins expressed by malignant cells but also found at lower levels in normal tissues. Vaccination strategies that target such antigens showed limited efficacy in late – phase clinical trials. & nbsp,
Researchers looked into neoantigens, or proteins that are only found in tumor cells, as potential targets for immunotherapy after learning that specific tumor mutations can produce them, according to Weber. The most promising vaccine strategies in oncology today, in my opinion, are neoantigen strategies. & nbsp,
Each patient’s tumor expresses a distinct set of neoantigens that can identify the cancer as foreign to the immune system, despite the fact that tumor-associated antigens are shared by the entire patient population. Neoantigen-based vaccines are therefore customized based on the unique genetic makeup of a patient’s tumor. In addition, & nbsp,
Vaccines for messenger RNA arrive in the fore & nbsp,
The platform used to deliver the target antigens is another crucial component of cancer vaccines. MRNA vaccines were being researched as a means of immunization against other infectious diseases and as an effective cancer treatment before the COVID-19 pandemic brought them into the spotlight. & nbsp,
MRNA-based vaccines have some advantages over other platforms, such as adaptability and production speed. Ryan Sullivan, MD, associate professor at Harvard Medical School and associate director of the Melanoma Program at Mass General Cancer Center, added that mRNA vaccines have intrinsic adjuvant properties that amplify the immune response because the body naturally detects and responds to exogenous mmRNA molecules. & nbsp,
Results from a personalized mRNA cancer vaccine’s first randomized phase II clinical trial were presented by Weber and Sullivan to demonstrate clinical benefit. & nbsp,
When compared to pembrolizumab alone, which is the standard of care adjuvant therapy in this patient population, the mRNA – 4157 / V940 vaccine, when administered in conjunction with the immune checkpoint inhibitor PEmbrOLIzumAb( Keytruda ), improved recurrence-free survival in patients with rectal, high-risk melanoma. Patients who received both pembrolizumab and mRNA-4157 / V940 had a 44 % lower risk of recurrence or death than those who only received pepomax. & nbsp,
The adjuvant setting, according to Weber, is perfect for this tactic because it allows for the analysis of the tumor tissue removed during surgery to find the most promising neoantigens, produce the vaccine, and give it to the patient while they are receiving standard-of-care treatment for their cancer. In addition, & nbsp,
Focused on tumor mutational burden( TMB ), tumor inflammation score, and PD-L1 expression, which are predicted to be associated with better outcomes, a biomarker analysis was conducted on baseline patient data. The study showed that these biomarkers had no bearing on the advantage brought about by the combination of the vaccine and pembrolizumab. In addition, & nbsp,
These results are very encouraging, according to Weber and Sullivan, and they imply that the neoantigen-based mRNA vaccine strategy may also be effective in other tumors. According to Weber, although the number of neoantigens varies greatly depending on the type of tumor, it may be possible to elicit antitumor immunity through an mRNA vaccine even in patients whose cancers express fewer of them. This is because algorithms can identify which genes are most likely to be immunogenic. & nbsp,
According to Weber,” This study is extraordinarily significant because it offers hope that this novel strategy will yield clinical benefits.” & nbsp,
The vaccine-pembrolizumab combination decreased the risk of distant metastasis or death by 65 % when compared to the vaccine alone, according to additional data presented at the 2023 American Society of Clinical Oncology Annual Meeting. & nbsp,
More patients are involved in a phase III trial to confirm phase II, which is anticipated to start by the summer of 2023. & nbsp,
Specifically addressing pancreatic cancer and nbsp,
A recently published study of another personalized mRNA-based vaccine tested in pancreatic cancer patients produced more encouraging results. & nbsp,
Senior author Vinod Balachandran, MD, assistant attending surgeon at Memorial Sloan Kettering Cancer Center, described pancreatic ductal adenocarcinoma ( PDAC ) as an example of an immunologically” cold” tumor with few mutation-derived neoantigens, few T cells, and no response to immune checkpoint therapy. In addition, & nbsp,
However, he added that about 9 % of PDACs are” hot” and infiltrated with activated neoantigen-specific T cells and other immune cells, traits found in patients who have exceptional long-term survival.
To understand why their tumors are hot and how this can be replicated in order to design therapeutic interventions, Balachandran and his team studied the neoantigens in long-term PDAC survivors. They discovered that T cells targeting those high-quality neoantigens persist long-term in PDAC survivors, as was previously explained in a previous post, and that some of these qualities predicted survival better than quantity. Because they give rise to long-term immunologic memory, these observations led to the creation of a neoantigen quality model and suggested that they would make ideal targets for an immunization strategy, according to Balachandran. In addition, & nbsp,
Balachandran and colleagues used an mRNA vaccine platform in a small clinical trial to quickly create an autogene cevumeran vaccine that specifically targets neoantigens from surgically resected PDAC tumors. They conducted tests to see if this vaccine could activate neoantigen-specific T cells and prevent recurrence. & nbsp,
Patients received one dose of the immune checkpoint inhibitor atezolizumab ( Tecentriq ) after surgery, then up to eight priming doses, the standard-of-care chemotherapy regimen for resectable PDAC, and finally a vaccine boost. Even after complex cancer surgery, as is necessary for PDAC, rapid custom vaccination is feasible and fully integrated into a standard oncologic workflow, according to Balachandran. & nbsp,
In eight out of 16 patients, autogene cevumeran induced de novo neoantigen-specific T cells. These reactions were strong, lasting two years after vaccination, with vaccine-induced T cells still present and accounting for up to 10 % of the total T cell in the blood. Additionally, there was a link between the vaccine response and the delay in recurrence at the follow-up period of 18 months. In addition, & nbsp,
As both responders and non-responders mounted good humoral and cellular responses to an mRNA vaccine against SARS-CoV-2 that was administered concurrently, Balachandran noted, the researchers found that the patients who did not experience a response were not less immunologically fit than those that did. Additional research revealed a link between the quality of neoantigens and vaccine response. & nbsp,
According to Balachandran, mRNA neoantigen vaccines may have a therapeutic effect in patients with pancreatic cancer, which has historically been thought to not contain mutation-derived antigens suitable for vaccinations. He continued by saying that these results laid the groundwork for a randomized phase II clinical trial that will take place soon in 2023. & nbsp,
Peptide-based vaccines and nbsp,
According to Catherine J. Wu, MD, FAACR, professor of medicine at Harvard Medical School and the Lavine Family Chair for Preventative Cancer Therapies at Dana – Farber Cancer Institute, another platform being investigated for neoantigen-targeted vaccination is based on peptides, which have a history of safety for use in patients and have been tested in several clinical trials. & nbsp,
A personalized vaccine with synthetic long peptides evaluated as adjuvant therapy in high-risk melanoma patients was shown to be feasible, safe, and immunogenic in a 2017 study by Wu and colleagues. Four of the six patients who received the NeoVax vaccine had no recurrence for up to 25 months. Immune checkpoint inhibitor therapy was then used to treat the two patients with recurrent disease, and within 12 weeks, they had a full clinical response, according to Wu. In addition, & nbsp,
Nearly four years after vaccination, a longer follow-up of the study’s participants revealed that, in addition to T cells reactive against epitopes that were not present in the vaccine, they were still circulating in their blood. This discovery, according to Wu, was evidence of epitope spreading or the emergence of additional T-cell responses against intracellular peptides released as a result of vaccine-induced tumor cell killing. & nbsp,
” These are all very encouraging results. In the field of cancer vaccination, there have been many ups and downs, but right now, things are going very well, according to Wu. She emphasized that the pandemic had taught us important lessons about how to deal with time, money, and getting vaccines to scale. & nbsp,
The first publication of the post-AACR Annual Meeting 2023: Clinical Trials of Therapeutic Cancer Vaccines Show Promise was made public by the American Association for Cancer Research.