Tumour Immunology Strategies

• cancer vaccines refers to therapeutic immunization in patients with cancer, with the main aim of breaking tolerance toward self-tumor-associated antigens. One strategy is to pulse antigen presenting cells such as  with tumor antigens in the hope that that such DCs will induce host protective and therapeutic antitumor immunity. 

The identification of the optimal antign to target for a pparticular tumour type has long been a priority for cancer immunotherpay. Tumour antigens can generally be categorized as being tumor associated which are overexpressed such as the HER2 receptor or tumour specific such as HPV which is associated with cervical cancer. (Hu, “Toward personalized, tumour-speciic, therapeutic vaccines for cancer” 2018). 

• Introduce genes encoding MHC Ags,  agonists, costimulatory molecules or into tumor cells. The goal here again is to improve the immunogenicity and the Ag-presenting capability of tumor cells. For example, DCs can be raised from bone-marrow stem cells upon culture with cytokine combinations. During the differentiation culture they can be transfected with recombinant viral vectors encoding cytokines like IL-12, IL-7, or IL-2. If such cells are then injected intratumorally they capture antigen, migrate to draining lymph nodes and orchestrate a potent CTL response. Artificial expression of the transgene greatly enhances the antitumor immune response. 

Interestingly, most of the pulsing has been done with peptides rather then proteins (which would require DCs to process the antigen). This is because when take DCs and put them into plastic culture dishes, giving them cytokines, etc., this matures them. So most of the DCs become mature. One way to counteracti this is to do this in viov. For example, FLT3L is a way to increase DCs in vivo to increase DCs prior to taking out the blood to grow the DCs in culture. Morese et al, JCO, 2001 found that if they systemically gaive Flt3 ligand to mice, DC population increased. Then use IL-14, GM-CSF and TNFa for growing the DCs (CD34+ HPC) in vitro.

Patients given subcutaneous GM-CSF administration increase mobilization of CD80+ DCs. Studies have shown that just giving GM-CSF is therapeutic. Newer treatments include taking tumor cells from patients, growing them, transfecting them with plasmid encoding with GMCF, then irradiating them to use them as a vacine. Trials have shown this stimulated DCs leading to increased CD8+ cells at tumor sites.

Another approach is to use TLR agonists to activate local immune response. For example, the TLR7 agonist, imidazoquinolines and TLR 9 CpG are being used to activate the innate immune system.

• Direct Tumor Transfection with Co-stimulatory Molecules: Another strategy is to take the tumor and turn it into an APC. Take tumor and put in rv-B7.1 to induce T cell activation and induce tumor recognition. Researchers have found that by doing this they were able to generate gp100- and MARt-1-specific T cells found in most A2+ patients.

• Adoptively transferring T Helper Cells to initiate CTL Immunity: Infusion of CD4+ T cell clones specific for P815AB reported shown tumor destruction through a CD8 mediated destruction. Other reports have shown that such transferring induces a broad immune response.

• Cancer Specific Antibodies: About 70 humanized monoclonal antibodies (mAbs) against tumor antigens are currently in human clinical trails, and 3 mAbs, Rituximab, herceptin and Alemtuzumab have been approved by the FDA. Although their mechanisms of action have been controversial, a major antitumor mechanisms of mAbs is thought to be by antibody-dependent cellular cytotoxicity (ADCC). mABs specific for tumor cell surface antigens bind to the tumor cell through their antigen binding domains and, through the Fc region of the mAb, bind to cells such as NK cells and neutrophils that express Fc receptors. This binding event is throught to activate the FcR-expressing cell, which results in ADCC.

• T Cell Activation with Treg Depletion: Knutson et al. 2005. Treg cells are known to express CTLA-4. Prudhomme G, J Luekocyte Biol, 2004 have given mice anti-CTLA4 and vacine against gp100. However, side effect get large autoimmunity.

• CAR T-cell Immunotherapy:  See outline

• Induce apoptosis. In models utilizing animals engrafted with human tumors, treatment with nduces significant tumor-specific apoptosis, tumor regression, and improved survival with no identifiable toxicity. TNF, LT-alpha1Beta2, FasL, and TRAIL are all expressed and used to kill cancer cells by professioanl cytotoxic cells, such as CD8+ CTLs and NK cells. In addition, Fasl, TNF, and TRAIL are expressed by activated CD4+ T cells, B cells and macrophages. Human immature DCs also express these TNF family ligands on their cell membrane. Cell surface expression and secretion of these cytotoxic ligands appears to be tightly regulated and differentiation stage-dpependent with the dendritic cell lineage. The possible regualtory mechanism might include activiteis of cytokines and/or metalloproteases.

• Induce phagocytosis. Cells undergoing apoptosis express specific signals, including lipids like phosphatidylserine (PS) that facilitate recognition and ingestion by macrophages. The possibility exists that one might be able to stimulate phagocytosis of tumor cells in the absence of a death signal to thereby delete cancer cells without even having any associated bystander effects observed during conventional chemotherapeutic treatment which is based on the induction of apoptosis.

• Attracting DCs to tumors with Chemokine: For example, injection of the chemokine CCL20 attracts DCs into the tumor, leading to induction of anti-tumor response. Intratumoral CpG can also activate tumor DC, leading to induciton of systemic anti-tumor immunity.
• Combination therapies: Strategies such as taregting multiple neopeitopes adncomining a personalized vaccines with complementary therapies will be important to prevent immune espacpe. For example, a mouse study showed that the comibnation of four components, a tumour antigen-targeting antibody, IL-2 aanti-PD1 therapy and a T cell vaccine) could liminate large tumour burdens. (Hu, “Toward personalized, tumour-speciic, therapeutic vaccines for cancer” 2018).