Success factors and new concepts of therapeutic cancer vaccines

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Success factors and new concepts of therapeutic cancer vaccines

Success factors and new concepts of therapeutic cancer vaccines.  Cancer vaccines usually include exogenous administration of selected tumor antigen binding adjuvants to activate DC, or use DC itself to make vaccines to activate the immune system and generate anti-tumor immunity.

The purpose of therapeutic cancer vaccines is to stimulate the patient’s immunity to specific tumor antigens, control tumor growth, induce tumor regression, and eradicate the smallest residual disease.

The basic elements of a successful cancer vaccine

• Provide DCs with a large number of high-quality antigens
• Best DC activation
• Induces enhanced and sustained CD4+ T helper cell and cytotoxic T lymphocyte (CTL) responses
• Good permeability of tumor microenvironment (TME)
• Maintain long-lasting tumor immunity

Several new considerations

• Reversing tumor-induced immune exhaustion with immune checkpoint inhibitors
• Injecting tumor-associated antigens and adjuvants to activate DC cells and effector T cells
• Autologous DC vaccine containing tumor specific antigen (TSA)
• In situ vaccines (ISVs), induce tumor cell death (ICD) through chemotherapy, oncolytic viruses, etc., and provide tumor-specific antigens; or inject immune activators (IL-2, IL-7, STING agonists) Etc.) to activate the local natural immunity and adaptive immunity of the tumor.

Although sipuleucel-T was approved 10 years ago, drug resistance caused by internal factors in tumor cells and systemic drug resistance caused by systemic immunosuppression made it only effective in advanced prostate cancer. Most of the clinical studies on tumor vaccines have also had negative results. The design of cancer vaccines may not take into account all the mechanisms that control immune neglect, rejection, suppression and escape. Therefore, these vaccines failed to produce a sufficient number of T cells and failed to elicit the durability of the T cell response required for sustained immunity.

Increase and expand the specificity of cancer vaccines

The success of antigen-specific therapeutic vaccines largely depends on the nature of the antigen in the vaccine.

For many years, common tumor antigens have been the focus of vaccine-targeted therapy. These genes include “self antigens”, such as cancer testis antigens, differentiation antigens, and overexpressed antigens, and virus-derived “non-self” antigens, such as high-risk human papillomavirus (HPV) E6 and E7 proteins.

“Neoantigens” are the focus of current research, including antigens produced in tumors, such as non-synonymous somatic mutations in the coding region (this mutation is also collectively referred to as “mutants”), human endogenous retroviruses, and In the microsatellite unstable high tumor or post-translational modification, such as phosphorylation, citrullination and glycosylation.

Neoantigen vaccine

To a large extent, the success of the neoantigen platform depends on the tumor mutation burden (TMB); that is, the number of mutations per megabase in tumor tissue. Tumors with high TMB may have a corresponding number of tumor rejection neoantigens for vaccine targeting and have a better response to ICI.

However, the corresponding high TMB and high ICI are not always the same. The reasons include: the inherent drug resistance mechanism of the tumor; the “quality” of the neoantigen (that is, the ability of the neoantigen to induce response to tumor TH1 cells and/or CTL) is directly related. These characteristics include: exogenousness, clonal distribution, biological characteristics of neoantigens, and appearance in MHC-I and MHC-II molecules, whether the mutation is a driving factor mutation, and T cell receptor affinity.

In addition to using tools to predict the “quality” of neoantigens, you can also use high-quality raw tissue materials, minimize coverage loss, accurate HLA classification, identify the serological activity and protein sequence of the antigen, and include MHC- II antigen to improve the accuracy of prediction.

New concept: non-antigen-specific in situ vaccines (ISVs)

Despite some successes, there are still some shortcomings in the selection of antigen vaccines, especially neoantigen vaccines, such as resource-intensive production processes, inability to cover all immunogenic epitopes, and ineffectiveness to emerging tumor epitopes.

ISVs are antigen-agnostic vaccines, not customized for a single mutant, but aimed at improving the endogenous anti-tumor response. The mechanism of ISV requires activation of immune cells in situ by stimulating innate immune pattern recognition receptors (PRRs) or other activation receptors on APC, inducing ICD, enhancing antigen presentation and enabling T cell activation and/or memory T cell activation .
Usually ISVs themselves can be used as drugs to activate PRRs.

• BCG vaccine, can activate TLR2 and TLR4, treat non-muscle invasive bladder cancer

• Imiquimod, a synthetic TLR7 and TLR8 agonist, is used to treat superficial basal cell carcinoma, and is super-indication for metastatic melanoma.

• FLT3L and CD40 receptor or CD40 agonists can improve DC mobilization and enhance proliferation to eradicate tumors and restore sensitivity to ICI. Although the use of FLT3L for single-agent therapy failed to cause clinical response, but the combination of FLT3L and other combinations has achieved good results.

• Oncolytic viruses have recently been introduced as ISV drugs that induce local and remote immunity. They can be genetically or chemically manipulated to express immunomodulators, such as cytokines, antibodies, and costimulatory factors. The ICD induced by the oncolytic virus releases tumor-associated antigens, including neoantigens, and promotes the activation of neoantigen-specific T cells. Talimogene laherparepvec (TVec) is the first and only oncolytic virus therapy approved by the FDA for the treatment of advanced melanoma, and is currently undergoing research as a combination therapy to improve clinical efficacy. Other viruses developed for oncolytic virus therapy include Coxsackie virus, Newcastle disease virus, adenovirus, poliovirus type 1, reovirus, vaccinia virus, measles virus and influenza virus.

• Stereotactic radiotherapy is another ISV method, which allows a low-separation radio beam to be precisely focused on the tumor target to induce ICD and promote anti-tumor response.

• Immune activating cytokines, such as GM-CSF, IL-12, IL-15 and IL-2, are very important to increase effective anti-tumor T cell and NK cell responses, and are very promising ISVs, especially for intratumoral injection in the case of. Agonists that selectively target IL-2R ((NKTR-214) and ALKS4230) are undergoing clinical trials. Through plasmid DNA electroporation, biodegradable microspheres, adenovirus, etc., these cytokines can be delivered intratumorally. Solid tumors are being studied, such as single-drug (NCT03323398) encoding IL-12 (MEDI1191), OX40L (costimulatory protein that promotes T cell activation) or binding to mRNA-encoded IL-23 and IL-36γ (NCT03739931).

In general, ISV may be a safe non-specific vaccine form with low off-target toxicity. They may stimulate a spontaneous immune response (automatic immunization), while increasing the ability to respond to other immunotherapies, such as ICI.

Success factors and new concepts of therapeutic cancer vaccines

(source:internet, reference only)

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