The future (Off the Shelf) of Cancer Vaccines building on the Past (Personalized)
(influenced by discussions at ASCO Breakthrough, Singapore 2026)
Cancer vaccines are broadly categorized into two main types:
· Preventive (Prophylactic) Vaccines: These target viruses known to cause cancer, such as the HPV vaccines (e.g., Gardasil), which prevent cervical and other virus-related cancers by stopping the initial infection.
· Treatment (Therapeutic) Vaccines: These are designed to treat existing cancers by training the immune system to identify and attack specific cancer cells. Provenge is the primary example of this.
The mechanism of action (MOA) for how Human Papillomavirus (HPV) causes cancer was discovered in the mid-1980s by German virologist Harald zur Hausen and his team. Zur Hausen first proposed the theory in 1976 and, by 1983, identified HPV 16 and 18. By 1985, his group had mapped the viral DNA and its carcinogenic mechanism.
The fundamental discovery defined how cancer-causing HPV strains hijack host cell operations through specific viral proteins:
- E6 Oncoprotein: Binds to and degrades the tumor suppressor protein p53. This prevents the cell from halting its division or triggering programmed cell death (apoptosis) in response to DNA damage.
- E7 Oncoprotein: Inactivates the retinoblastoma protein (pRb). This forces the cell to divide and replicate its DNA uncontrollably.
Because of this breakthrough regarding viral oncogenesis and its role in cervical cancer, zur Hausen was awarded the 2008 Nobel Prize in Physiology or Medicine.
One aspect of these first cancer vaccines was the fact that RNA splicing and missplicing play an integral role in how human papillomavirus (HPV) causes both cervical and head and neck cancers. The next step (beyond viruses) in early cancer vaccines relied heavily on neoantigens—unique proteins generated by tumor-specific genetic mutations. They became the preferred target for early immunotherapy development to solve two critical problems that plagued earlier, less successful vaccine generations.
The core idea of neoantigens in cancer immunotherapy is to bypass central immune tolerance. Because neoantigens are mutated proteins found only on tumor cells and absent in healthy tissues, the body’s immune system recognizes them as strictly “foreign,” making them ideal targets to trigger highly specific, targeted anti-cancer responses. Normally, the immune system avoids attacking healthy cells through immune tolerance.
During T-cell development, the body deletes or silence T-cells that react to normal “self” proteins. Because tumors develop from the patient’s own cells, older immunotherapy methods that targeted normal, unmutated “tumor-associated antigens” often failed because the body’s tolerance mechanisms would hold the T-cells back. Neoantigens solve this by providing a truly unique, mutated.
This led to the early development of Personalized Neoantigen Vaccines: Therapies, such as mRNA vaccines, analyze a patient’s specific tumor mutations and train the immune system by presenting these unique neoantigens to antigen-presenting cells, prompting T-cells to multiply and hunt down the cancer.
· Adoptive T-Cell Therapies: A patient’s own T-cells are extracted, genetically engineered in a laboratory to specifically recognize the patient’s tumor neoantigens, and then multiplied and infused back into the body.
· The Past Failure: Early cancer vaccines often targeted tumor-associated antigen proteins like HER2 or MUC1 that are simply overexpressed. Because these are essentially “self” proteins, the body’s immune system naturally tolerates them to prevent autoimmune damage, making them ineffective at inciting a strong tumor attack
- · The Neoantigen Advantage: Neoantigens result from DNA mutations that are strictly absent in normal, healthy tissue. Because the body views these mutated proteins as completely foreign (“non-self”), they can bypass the body’s natural immune tolerance mechanisms and trigger high-affinity T-cell responses.
While neoantigens offered a precise and highly immunogenic target, their limitation is that tumors can sometimes mutate further to hide them or create immunosuppressive environments that blunt the immune response. As a result, modern neoantigen vaccines are often combined with Immune Checkpoint Inhibitors to ensure the activated immune cells can successfully eliminate the cancer.
Early neoantigen cancer vaccines (2012–2019) struggled primarily because they were limited by slow, pioneering manufacturing techniques, an inability to overcome aggressive tumor-driven immunosuppression, and unpredictable predictive algorithms that often selected non-functional neoantigens.
Key reasons for the modest clinical results during this period include:
- Tumor Microenvironment (TME) Suppression: Vaccines successfully trained the immune system to generate T cells, but these cells were quickly suppressed by the tumor’s natural defenses, including regulatory T cells (Tregs) and immunosuppressive cytokines.
- Algorithm Immaturity: Early bioinformatics pipelines were highly inaccurate at predicting which mutations would actually be processed, presented by the Major Histocompatibility Complex (MHC), and recognized by T cells.
- Tumor Heterogeneity: Because vaccines were often designed based on bulk tumor biopsies, they frequently targeted antigens present only in dominant clones. This allowed surviving cancer cells lacking those specific mutations to multiply and evade the immune system.
- Manufacturing Delays: Personalized vaccines require sequencing a patient’s tumor and manufacturing the vaccine from scratch. Between 2012 and 2019, this process was too slow, often taking several months, which allowed aggressive cancers to progress faster than the vaccine could be delivered.
- Immune Evasion Mechanisms: Tumors frequently mutate to downregulate their MHC molecules, effectively hiding the targeted neoantigens from the immune system’s cytotoxic T cells.
- The reason many of these vaccine failures occur is that a number of critical obstacles remain to be overcome before neoantigen vaccines can deliver clinical benefit. These obstacles relate to neoantigen selection, vaccine platform, adjuvant potency, T cell recruitment and function, and tumor microenvironment.
Developing a successful neoantigen cancer vaccine has historically been challenging, primarily due to the high mutational variability of tumors and manufacturing bottlenecks. While early attempts in advanced or bulky metastatic disease often failed to meet their primary endpoints, they paved the way for today’s industry-standard adjuvant (post-surgery) therapies. Some of the companies that have discontinued specific neoantigen or custom tumor vaccine programs due to clinical setbacks include: Gritstone bio, Argos Therapeutics, Celldex Therapeutics, CureVac, Agenus, and Neogen.
How tracking RNA mis-splicing allowed scientists to discover tumor-specific neoantigens—unique, mutated proteins produced by cancer cells due to splicing errors. By identifying which of these mis-spliced proteins are shared across broad patient populations rather than being unique to one person, researchers developed off-the-shelf mRNA vaccines capable of universally targeting specific cancer types.
Here is the step-by-step breakdown of how this discovery revolutionized cancer vaccine development:
1. Identifying the Source of “Hidden” Antigens
· The Problem: Early cancer vaccines were targeted at patient-specific DNA mutations. While highly effective, manufacturing these bespoke vaccines required sequencing an individual’s tumor and took weeks to months to synthesize, making them impractical for fast-growing cancers.
· The Splicing Discovery: Researchers found that cancer cells frequently make errors when editing their mature RNA. This mis-splicing acts like an editing typo, leading the cell to manufacture unique proteins (neoantigens) on its surface that healthy cells do not possess.
2. From Personalized to Off-the-Shelf
· Shared “Typos”: Through large-scale multi-omics and RNA sequencing data, scientists realized that certain mis-splicing events are incredibly common across different patients and tumor types (e.g., hepatocellular carcinoma or gliomas).
· Broader Coverage: Because these mis-spliced transcripts frequently result in shared public neoantigens, researchers no longer had to create a bespoke vaccine from scratch for every single patient. Instead, they can encode the mRNA for these shared cancer-specific targets into mass-producible, off-the-shelf products.
3. How the Vaccines Work in the Body
· Immune Reprogramming: The synthetic mRNA for these mis-spliced proteins is packaged inside microscopic fat droplets called lipid nanoparticles.
· Targeted Attack: Once injected, the mRNA instructs the patient’s cells to display the cancer-specific protein on their surface. The immune system recognizes this protein as foreign and deploys cytotoxic T cells to seek out and destroy tumors displaying those exact neoantigens.
Tumoral RNA splicing generates aberrant transcripts that are translated into tumor-specific neoantigens. Because these splicing aberrations (such as altered exon skipping or intron retention) often create shared, tumor-wide neojunctions across multiple patients, they bypass the need for strictly patient-specific targets, offering a promising foundation for “off-the-shelf” cancer immunotherapies.
Mis-splicing helps identify “real” (bona fide) neoantigens by uncovering tumor-specific RNA alterations—such as exon skipping or intron retention—that create highly distinct, foreign-looking protein sequences. These aberrant junctions are often tumor-wide and highly immunogenic. Mis-splicing aids in the hunt for actionable cancer targets in several key ways:
· Bypassing Limitations of DNA Mutations: Standard DNA sequencing only flags a small fraction of immunogenic neoantigens (like single-nucleotide variants). Splicing changes create brand-new, cancer-specific exon-to-exon junctions (neojunctions) that serve as distinct targets for T cells.
· Confirming Actual Expression: Bioinformatic pipelines like analyze RNA sequencing data to confirm that these mis-spliced transcripts are actively produced
· Evading Self-Tolerance: Because these mis-spliced transcripts result in entirely unique amino acid sequences, they appear foreign to the immune system, allowing T cells to recognize and attack tumor cells.
· Targeting Shared Neoantigens: Specific mutations in the splicing machinery (common in leukemias and other cancers) cause reproducible, shared mis-splicing events across different patients. This provides targets for “off-the-shelf” T-cell therapies rather than requiring fully personalized designs.
Some of the cancers most strongly linked to RNA splicing errors include:
Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) are heavily driven by mutations in core splicing factor genes (such as SF3B1, U2AF1, and SRSF2). . These mutations lead to recurrent mis-splicing, generating actionable neoantigens that serve as targets for emerging immunotherapies.
Lung Cancer: Both non-small cell lung cancer (NSCLC) and lung adenocarcinoma frequently exhibit aberrant splicing, including the well-known MET exon 14 skipping mutation.
Breast Cancer: Highly adaptable splicing patterns are known to drive tumor growth and treatment resistance across various subtypes.
Pancreatic Cancer: RNA splicing dysregulation enables pancreatic cancer cells to be highly adaptable, resistant to treatment, and to multiply rapidly.
·Prostate Cancer: Specific mis-splicing events and over-expression of splicing factors (such as the hnRNP family) are linked to the rapid proliferation of tumor cells.
The Future of Off-the-Shelf Cancer Vaccines: Progressing Beyond Personalized Strategies
The main problems with these early vaccines were slow, experimental production, an inability to overcome strong tumor-induced immunosuppression, and computer programs that often selected ineffective neoantigens. Several critical factors contributed to the modest clinical outcomes observed during this period:
- Tumor environment suppression: Even though vaccines increased T cell numbers, these immune cells were rapidly suppressed by the tumor’s own defenses, including regulatory T cells (Tregs) and other immunosuppressive factors.
- Immature algorithms: Early computer methods often could not accurately predict which mutations would be presented by the major histocompatibility complex (MHC) and recognized by T cells.
- Several critical obstacles must be addressed before neoantigen vaccines can achieve substantial clinical benefit. These challenges include neoantigen selection, vaccine platform optimization, adjuvant potency, T cell recruitment and function, and the tumor microenvironment.
Watching RNA mis-splicing has helped scientists find tumor-specific neoantigens, which are unique mutated proteins produced by cancer cells due to splicing errors. By identifying which mis-spliced proteins are common across many patients rather than unique to one person, researchers have created off-the-shelf mRNA vaccines that can target specific cancer types in many people. The following is a step-by-step overview of how this discovery transformed cancer vaccine development. Identification of the Source of “Hidden” Antigen: Researchers found that cancer cells often make errors when editing mature RNA. This mis-splicing acts like a typo, causing the cell to produce unique proteins (neoantigens) on its surface that healthy cells do not have.
Transition from Personalized to Off-the-Shelf Vaccines: Shared Splicing Errors: Large-scale studies of multiple biological data types and RNA sequencing have shown that some mis-splicing events are very common across different patient groups and tumor types, such as liver cancer and brain tumors.
Broader Coverage: Because these mis-spliced RNA pieces often produce shared neoantigens, researchers do not need to make a custom vaccine for each patient. Instead, the mRNA for these shared cancer targets can be included in mass-produced vaccines, allowing wider use.
Immune Reprogramming: The synthetic mRNA encoding these mis-spliced proteins is wrapped in tiny fat particles for delivery.
Targeted Immune Response: After vaccination, the mRNA instructs the patient’s cells to display the cancer-specific protein on their surface. The immune system recognizes this protein as foreign, prompting cytotoxic T cells to identify and destroy tumor cells expressing these neoantigens.
Tumor RNA splicing generates abnormal RNA fragments that are processed into tumor-specific neoantigens. Splicing mistakes, such as skipping parts of RNA or retaining extra parts, often create shared new junctions across many patients, removing the need for fully patient-specific targets and helping to develop off-the-shelf cancer immunotherapies.
Mis-splicing helps identify true neoantigens by revealing tumor-specific RNA changes, such as skipping or retaining RNA segments, that generate highly unique and immune-activating protein sequences. These abnormal junctions are often found throughout the tumor.
Mis-splicing contributes to the identification of actionable cancer targets in several key ways:
Bypassing the Limits of DNA Mutations: Regular DNA sequencing identifies only a small subset of immune-activating neoantigens, such as single-letter changes. Splicing changes create new, cancer-specific exon-to-exon junctions (neo junctions) that act as clear targets for T cells. Computer analysis of RNA data checks that these mis-spliced RNAs are actually made.
Evading Self-Tolerance: These mis-spliced RNAs make completely unique protein sequences, making them foreign to the immune system and allowing T cells to spot and attack tumor cells.
Targeting Shared Neoantigens: Certain mutations in the splicing process, common in leukemias and other cancers, cause repeatable, shared mis-splicing events across patients. This enables the creation of off-the-shelf T-cell therapies rather than fully personalized ones.
Several cancers are strongly associated with RNA splicing errors, including:
Blood Cancers:
Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) are greatly affected by mutations in key splicing factor genes, like SF3B1, U2AF1, and SRSF2.
These mutations cause repeated mis-splicing, creating targetable neoantigens and making them good targets for new immunotherapies.
Lung Cancer: Both non-small cell lung cancer (NSCLC) and lung adenocarcinoma often show abnormal splicing, including the MET exon 14 skipping mutation. Breast Cancer: Flexible splicing patterns help tumors grow and resist treatments in different subtypes.
Pancreatic Cancer: Problems with RNA splicing let pancreatic cancer cells adapt, resist treatments, and grow quickly. Prostate Cancer: Certain mis-splicing events and too much splicing factor activity (like hnRNP family members) are connected to fast tumor growth.
The Result: The exact variant controls how severe the cancer is. For example, the S34F variant alters the activity of hundreds of genes, producing shorter RNA fragments that evade normal breakdown, helping tumors survive. The best way to prevent or treat cancer caused by RNA problems, such as mis-splicing, is with precise therapies that target either the splicing process or specific mis-spliced RNAs. Since cancer cells depend on altered splicing to grow and survive, drugs can take advantage of this weakness. RNA mis-splicing uses two main targeted strategies:
Splice-Switching Antisense Oligonucleotides (ASOs): ASOs are man-made strands of genetic material that attach to specific mis-spliced RNA sequences. They “trick” cells into skipping faulty splicing instructions (such as adding “poison exons”) or into breaking down the mutant RNA, which effectively stops the cancer cell’s growth signals. Other changes in RNA sequences that introduce new amino acids (such as frameshift errors) can be harnessed to design vaccines. These novel proteins—called neoantigens—are recognized as “foreign” by the immune system, making them highly effective targets for both cancer immunotherapies and infectious disease vaccines.
How this works for vaccine design
· Cancer Vaccines: Tumors often have genetic errors that cause their cells to produce mutant or frameshifted proteins. Researchers use these unique amino acid sequences to create preventive and therapeutic “off-the-shelf” vaccines, teaching the immune system to hunt down and destroy cancer cells.
· Viral Vaccines: RNA viruses inherently mutate rapidly, continually introducing new amino acids into their surface proteins to evade the immune system. Scientists harness this information to develop updated, broad-spectrum mRNA vaccines that anticipate mutations and quickly neutralize new variants.
The science behind the concept
· Frameshift Peptides: When the RNA “reading frame” is shifted by an insertion or deletion of nucleotides, the cell translates entirely new strings of amino acids. Because these sequences do not exist in healthy cells, they trigger a remarkably strong immune response.
· Translating into Action: Modern platforms, such as those detailed in Nature, allow scientists to rapidly adjust the genetic sequences in mRNA vaccines to match emerging viral variants or target specific cancer mutations.