The therapeutic application of messenger RNA (mRNA) has ignited significant optimism in the pursuit of curing challenging diseases like cancer. Our group has translated a novel personalized therapeutic mRNA lipid nanoparticle cancer vaccine from preclinical studies to first-in-human clinical trials for brain cancer. We have demonstrated vaccine efficacy in head and neck cancer preclinical models and pet felines with oral cancer, and are planning a Phase I clinical trial for patients with recurrent/metastatic head and neck cancer.

• What are the most promising strategies to identify and target tumor-specific antigens using cancer vaccines?
• What are the most effective vaccine delivery platforms for cancer therapy?
• What role do combination therapies play in overcoming immunosuppression and maximizing the effectiveness of cancer vaccines?
• How can cancer vaccines be successfully integrated into standard of care cancer treatment?
  

Most patients fail to respond to checkpoint blockade, partly due to a lack of preexisting anti-tumor immunity, and cancer vaccines aim to induce de novo anti-tumor immune responses. In situ vaccines—creation of an immune response within a tumor, against tumor antigen—offer the potential for a polyclonal, inherently personalized priming of antitumor immunity against optimal targets. We have previously shown DC1 to be necessary for response to checkpoint blockade, and so we use Flt3L to augment DC1 infiltration after releasing tumor antigen using low-dose palliative radiation. These DCs are then activated with poly-ICLC, and vaccine efficacy further potentiated with pembrolizumab.

Stresses within the tumor microenvironment mediate post-translational modifications of self-proteins. Homocitrullination is the conversion of lysine residues to homocitrulline which can generate neoepitopes and bypass self-tolerance. Modi2, a homocitrullinated peptide-SNAPvax vaccine, stimulates strong Th1 responses and anti-tumor immunity in three different murine tumor models. We propose the Modi-2 vaccine formulation has potential for translation into clinic in several cancer indications.

Elenagen is a plasmid encoding p62/SQSTM1. In randomized clinical studies, Elenagen significantly increased the progression-free survival (PFS) of platinum-resistant ovarian cancer patients receiving gemcitabine chemotherapy. The highest effect was in the patient's subgroup with the worst prognosis. Also, Elenagen demonstrated promise for the treatment of breast cancer. 

Elenagen alters the tumor microenvironment, turning “cold” tumors into hot ones. Thus, it can potentially become an adjuvant to immuno-, chemo-, and radiation therapies that require intratumoral lymphocyte penetration.

Promising for the treatment of cancers and other inflammatory diseases, Elenagen mitigates systemic chronic inflammation. 

Elenagen acts indirectly via modulating MSCs and macrophages.

PD-1 inhibitors have modest efficacy as monotherapy in hepatocellular carcinoma. A personalized therapeutic cancer vaccine (PTCV) tailed against neoantigens may enhance responses to PD-1 inhibitors through the induction of anti-tumor immunity. Clinical data highlighting objective responses and vaccine-induced immune responses will be presented. Critical factors for successful translation of personalized therapeutics into the clinic will also be discussed.

Immune checkpoint therapies targeting the PD-1/PD-L1 fail in most patients. While there are several reasons for failure, correlative research in many trials suggest that a lack of a pre-existent immune response is in large part responsible. One solution to augmenting pre-existing immunity is with cancer vaccines. This seminar will discuss recent studies evaluating the hypothesis that combination vaccine and immune checkpoint blockade therapy is more effective than either strategy alone.

In this phase I study, we tested the safety and immunogenicity of a peptide-based vaccine targeting the six most common KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) in combination with ICIs in patients with resected PDAC. Among 12 vaccinated patients, 11 patients generated a statistically significant increase in the average mKRAS-specific T cell response and 10 patients generated a significant tumor-specific mutation response. The vaccine induced de novo mutant KRAS-specific Th1 CD4 and cytotoxic CD8 T cells with an acceptable safety profile. We also defined here a novel repertoire of mono-, cross-reactive, and public mutant KRAS-specific T cell clonotypes.

While cancer immunotherapies have revolutionized the treatment of cancer patients, there are still many patients who receive no clinical benefit. Several successful clinical trials utilizing personalized neoantigen vaccines have been conducted. However, these trials primarily target patients with high-TMB cancers, such as melanoma, as low-TMB cancers are less likely to have targetable neoantigens. Looking beyond neoantigens has the potential to make personalized cancer vaccines relevant for more patients.

Neoantigen-directed immunotherapies typically rely on short-read exome sequencing to catalog the coding mutations in a cancer's genome. This original sin dooms all downstream filtering and predictive modeling to mostly consider SNVs while discarding the larger mutations which may better distinguish cancer from self. Long-read sequencing, on the other hand, allows us to resolve a broader spectrum of protein altering genomic events which serve as a richer basis for neoantigen discovery.

Here I will discuss the design and development of combinatorial synthetic bioreducible and biodegradable lipid nanoparticles (LNPs) with distinct chemical structures and properties for mRNA delivery with organ and cell selectivity. I will show an example of using this system for delivery of mRNA cancer vaccine. mRNA cancer vaccine is based on our LNPs elected robust CD8+ T cells response, excellent therapeutic effect, and long-term immune memory.

mRNA vaccines and therapies have transformed medical approaches to infectious diseases, genetic disorders, and oncology. We present two key advancements of the field: non-invasive mRNA delivery via stabilized, lung-optimized lipid nanoparticles for pulmonary applications, and the enhancement of immune responses in mRNA vaccines through integration of multiple, novel adjuvants. These studies combined significantly broaden the therapeutic scope of mRNA technology.