The opportunities and challenges of pancreatic cancer immunotherapy

Pancreatic catheterization (PDA) is the most common type of pancreatic cancer, with a high fatality rate and poor prognosmation.
treatment of PDA has always been a very difficult challenge in clinical research.
that PDA will become the second-largest cause of cancer-related deaths by 2030 as PDA morbidity continues to rise and mortality rates change dramatically.
only a few patients with removable PDAs are able to achieve long-term survival through surgery and complementary chemotherapy.
PDA is almost completely resistant to FDA-approved immunotherapy, which has been defeated almost repeatedly on the PDA mountain in patients with advanced solid tumors such as melanoma and lung cancer.
December 14th, in a review by Canser Cell, researchers at the Perelman School of Medicine at the University of Pennsylvania reviewed the new immunotherapy that the PDA is working on and discussed promising treatment strategies for the future.
resistance to immunotherapy through PDA, the intrinsic immune resistance mechanism of tumors, is driven by its unique genetic map.
PDA genetically engineered mouse models such as KC and KPC mice greatly enhance our understanding of PDA tumors and contribute to the discovery of preclinical immunotherapy drugs.
For example, the researchers used these mouse models to define pancreatic catheter epithelitis (PanIN) as a mutation initiated by the mutated KRAS (mKRAS) that develops into an invasive cancer after tumor suppression gene insisnation.
human PDA exon group has validated the high prevalence of KRAS-activated mutation expression.
of mKRAS gene expression due to allelic gene imbalance may be a key determining factor in PDA progression and metastasis.
Although there are common pathogenic paths to cancer with other types of cancer, PDA is a genetic heterogeneous disease with different clinical esoteric forms, and genetic and presumed genetic changes give it distinctive molecular, cellular and clinical characteristics.
1 shows the immunosuppressive network formed by the downstream signal conduction of mKRAS.
growing body of research suggests that mKRAS, in addition to its classic carcinogenic effects, drives the establishment of immunosuppression within TME.
mKRAS directly blocks congenital and adaptive anti-tumor immunity by enhancing autophagy to regulate the level of the main tissue-compatible complex I (MHC-I) on the cell surface and by regulating the expression of CD47 and PD-L1.
addition, mKRAS coordinates side secretion networks to establish TME consisting of immunosuppressive cells, active substitino cells, and connective tissue procreation, and TME evolution occurs before invasive cancers are formed.
can be observed in KC mice, PanIN lesions are immersed in immunosuppressive tumor-related macrophages (TMs), myelin-source inhibitory cells (MDSCs), and regulatory T-cells (Tregs).
Immune Resistance to PDA (Source: Cancer Cell) Targeting mKRAS signaling may promote an anti-tumor immune response.
In the engineered CT-26 mouse tumor model, inhibition of KRAS G12C increased the expression of MHC-I in tumor cells and promoted the immersion of T-cells in TME, increasing the sensitivity of tumors to immunomodulation.
However, KRAS G12C mutations are rare in PDAs, and other, more common mKRAS variants do not have targeted therapies, but studies in the field of alternative therapies such as engineering exosomes and mKRAS-specific T-cells have shown promising results and are expected to benefit PDA patients in the future.
PDA's primary resistance to immune checkpoint blocking target CTLA-4 or PD-1/L1 immuno checkpoint blocking therapy, whether single or combination, has limited therapeutic activity in late-stage PDA.
may be a lack of strong pre-existing T-cell immunity in the body.
in patients with PDA who were treated for the first time, naturally occurring T-cell responses were limited.
factors that limit the naturally occurring T-cell immunity in PDA are the low expression of MHC-I and the inhibition of T-cell initiation and function mediated by TME.
the use of combination therapies to give antigen specificity, enhanced T-cell function and tumor recognition may increase PDA sensitivity to immuno-checkpoint blocking therapy (Figure 1).
In preclinical models, the use of autophagy inhibition to restore tumor cell MHC-I expression or the use of CD40 single-anti-excitation tumor-specific T-cell immunity can enhance PDA response to immuno-checkpoint blocking therapy.
the strength of antigen strength of PDA tumor determines the immune response strength of tumor, and the intensity of antigen expression of PDA is low.
without strong antigens, no significant immunosuppression and immune editing were observed in the KPC mouse model.
that non-synonymic mutations during tumor occurrence produce new antigens for tumor cell-specific expression.
a moderate burden of non-synonymic new antigen mutation in human PDA tumors and was associated with patient survival.
, new antigens are rarely shared among patients, limiting the development of new antigen-targeted therapies, so PDA patients may need more time-consuming and expensive personalized therapies.
the ideal target antigen for tumor antigen mKRAS should be specific to tumor cells and be essential to tumor pathogenesis.
in PDAs, soda cell mutations in cancer-driven genes meet these criteria.
non-synonym mutations occur in more than 90% of human PDAs, and the mutation points are almost all G12 cophers.
TP53 inerties occur ∼ 70% of PDA cases.
cancer vaccine has long been exploring the use of mutant KRAS and p53 as therapeutic targets.
Although some patients may be induced to respond to T-cells of mKRAS and p53 after receiving targeted therapy, most studies have not been sufficient to demonstrate the clinical benefits of targeting mKRAS and p53, nor have they clearly defined the restrictive immunogenic table of human leucocyte antigen (HLA).
a recent study in the model of HLA genetically modified mice suggests that mKRAS immune targeting may be suitable for patients of certain HLA types.
therefore, to advance the wide range of clinical applications of therapy, there is a need to better understand the combined properties of mKRAS antigen processing and delivery, as well as antigen meso-HLA.
-stimulating PDA-specific immunotherapy The activation patterns of chemotherapy, radiotherapy, and congenital immunity, such as tooll-like subjects (TLRs) and cyclic GMP-AMP synthases (cGAS), are expressed on the surface of congenital immune cells, detecting and identifying pathogen-related molecular patterns (PAMP) and damage-related molecular patterns (DAMPs), prompting the expression of inflammatory cytokines and I-type interferon (IFN) to activate adaptive anti-tumor tumors.
There is research evidence that chemotherapy and radiotherapy make tumors sensitive to immuno-checkpoint blocking therapy by releasing PAMP and DAMP to promote the activation of TLR-dependent and interferon-dependent dextatin-dependent degenerative cells.
the tumor killer properties of chemotherapy and radiotherapy work in synergy with immunotherapy to expand the TCR library and enhance T-cell immersion of tumors by increasing the expression of MHC-I, cross-transmission of antigens, and T-cell initiation.
in PDA clinical trials, combining chemotherapy or radiotherapy with immunotherapy is also active (Table 1).
Table 1 PDA clinical trial based on immunotherapy Source: Cancer Cell Cancer Vaccine Cancer Vaccine is a new type of immunotherapy.
early studies targeting mKRAS, cancer embryo antigens (CEA), mucous protein 1 (MUC1) and telomerase have shown that cancer vaccines induce antigen-specific immunity and prolong the survival of immune responders.
, however, in several validated vaccine trials targeting telomerase or EGFR2, the clinical benefits to patients with advanced PDA were not demonstrated, although the vaccine induced T-cell immunity.
vaccine is an ad-side therapy that is expected to improve clinical efficacy in an environment with minimal tumor burden and TME immunosuppression.
mKRAS adsive peptide vaccine study conducted in PDA patients caused an immune response in most patients and was associated with improved survival rates.
Vaccination may increase the sensitivity of tumors to immuno-checkpoint blocking therapy, and compared to either therapy alone, vaccine/immune checkpoint blocking combination therapy promotes T-cell immersion of tumors and overcomes T-cell depletion, inducing long-lasting tumor retreat.
There was a correlation between step-by-step T-cell therapy T-cell immersion and improvement of PDA clinical outcomes, and PDA tumors were immersed to varying degrees by CD4-plus and CD8-T cells, which tended to reside in the substitiotic region outside the tumor core.
preclinical studies have demonstrated the feasibility of separating and in vitro amplification of tumor inocular leaching lymphocytes (TIL) from PDA tumor specimens.
, however, most PDA patients lack pre-existing T-cell immunity, which may limit the applicability of TIL therapy in the PDA patient population.
car-T cell therapy and TCR-T cell therapy have brought unprecedented clinical changes to patients with blood malignancies.
, however, the success rate of this type of step-by-step T-cell therapy in the field of solid tumors is relatively low.
researchers are enhancing the homecoming, penetration and persistence of T-cells by combining immunomodulants or expressing genetically modified organisms to increase the activity of these therapies in solid tumors.
addition, gene editing is also carried out through CRISPR/Cas9 technology to increase the expression of genetically modified receptors or to enhance the anti-tumor activity of transgenic T-cell therapy by increasing the expression of inhibitory signaling molecules.
limitation of the application of CAR-T and TCR-T cell therapy to PDAs is the choice of antigens.
to date, most studies have targeted tumor-related antigens (TAA), and the variability or heterogeneity of TAA's expression on tumor cells may pose a greater risk of off-target toxicity.
the antigen targets targeted by CAR-T therapy being studied in PDA are mesothelocytes, prostate stem cell antigens, cancer embryo antigens (CEA), mucous protein 1 (MUC1) and human epidermal growth factor 2 (HER2).
adverse events have occurred in patients treated with T-cell products that target HER2 and CERA, limiting the evaluation of these antigens in the CAR-T therapeutic PDA.
However, CAR-T, which targets mesothylphotin, showed efficacy in preclinical mouse models and safety in early clinical studies in patients with chemotherapy refrupable metastasis PDA, which is worth continuing clinical evaluation (Table 1).
high expression and conservative mutation characteristics of mKRAS in PDA provide a unique opportunity to develop new antigen-targeted TCR therapies with wide universality.
potential for the treatment of step-by-step T-cell therapy targeting mKRAS new antigens has been reported and further clinical trials are under way (Table 1).
-targeted myelin cells myelin cells are the main components of TME, consisting of TAM, polygonal nuclear MDSC and single-core MDSC, which play an immunosuppressive role in TME and are essential for tumor occurrence and immune escape.
Blocking Theset Stimulation Factor-1 Subject (CSF-1R) reprograms TAM to promote antigen delivery and the initiation of anti-tumor T-cell response, and the combination of CSF-1R blocking and immuno-checkpoint blocking therapy can greatly enhance anti-tumor activity.
, however, a clinical Phase II study evaluating the efficacy of CSF-1R monoantigen cabirizumab and Navuliyu monoantigen and chemotherapy in patients with advanced PDA did not improve progression-free survival compared to chemotherapy alone (NCT03336216) (Table 1).
addition, cell dissolution activity in lymphocytes is associated with the expression of a variety of immuno checkpoint genes in the PDA, including CTLA4, TIGIT, TIM3, and VISTA.
, VISTA is expressed on TAM and is rich in PDA, which is associated with PDA resistance to immunotherapy, and inhibition of VISTA may improve PDA's response to TAM-targeted therapies.
It is worth mentioning that the non-carcinogenic path path of PDA tumors also mediates the immersion of myelin cells, such as epoxyase-2 (COX2) can promote the expression of factors such as cyclic factor CXCL1, establish a "cold" TME, COX2 inhibition has been shown to be clinically feasible.
authors of the review speculate that myelin immunosuppression is the dominant immune checkpoint in PDA.
target substation composition hyaluronic acid is the main component of PDA substation, through hyaluronic acid enzyme PEGPH20 to hyaluronic acid enzymatic, can reduce the interstate pressure in KPC mice, enhance the efficacy of chemotherapy.
potential substitut targets include the overactivation of plaque kinase (FAK), vitamin D subject (VDR), and fibroblast activation protein (FAP).
in PDA promotes fibrosis and immunosuppression of TME.
clinical trials of the fak inhibitor joint PD-1-antibody are under way (Table 1).
Giving vitamin D similarities can induce the reshaping of the base of KPC mice and enhance chemotherapy responsiveness, vitamin D deficiency is associated with a decrease in PDA survival, and clinical studies are under way to combine vitamin D similarities with immuno-checkpoint blocking therapy (Table 1).
that FAP is overexposed in tumor cells and substitin fibroblasts and is associated with adverse outcomes of PDA.
the removal of FAP expression in mouse models of lung cancer and PDA improved tumor response to vaccine and immune checkpoint blocking, highlighting the immunosuppressive effect of FAP expression cells.
CAR-T therapy, which targets AFP, also showed anti-tumor activity in cancer mice, including KPC mice.
in the earliest stages of PDA tumor start-up, cancer drivers promote immunosuppression and reduce T-fine