Her2 can heterodimerize with other members of the family, mediating cell growth and proliferation by activation of the MAPK and PI3K pathways. CD24 is a GPI-sialoglycoprotein anchored to the cell surface, and it is essential for the growth and differentiation of granulocytes and B cells. Both antigens have been targeted by a CAR-T cell approach. Maliar et al.
Treatments were also effective against high tumor burden and multiple metastases [ ]. Unfortunately, a metastatic colon cancer patient treated with a third-generation CAR targeting Her2 died because of respiratory failure due to the recognition of Her2 in the lung epithelium [ ]. The strong potency of CARs reduces the timeframe, after which antigens expressed on healthy tissues are targeted, increasing off-target toxicity. To extend this timeframe, Raj et al.
In vitro experiments confirmed how switchable CAR-T cells were able to lyse both patient-derived tumor cells and cancer stem cells [ ]. Tumor cell growth was monitored with live imaging and after 17 days, when tumors were detectable, mice were enrolled for treatment. Treatment with inactive Fab was ineffective, but at day 10, mice administered with either switchable or conventional CAR-T cells were tumor- and metastasis-free [ ].
CEA, discovered by Gold and Freedman in [ ] , is a cell surface protein with a GPI domain and is expressed from an early fetal period weeks throughout life. CEA can act as a homophilic or heterophilic adhesion tool in cancer cells [ ]. CEA was previously exploited as a target in other immunotherapeutic strategies such as vaccines, while the CAR approach for this antigen began in Chmielewski et al.
This strategy avoided dose-limiting autoimmune colitis and pneumonia observed in a pilot study for metastatic colorectal cancer [ ]. Panc02 pancreatic carcinoma cells were injected into the pancreas of immune-competent transgenic mice, expressing CEA in the gastrointestinal and pulmonary tracts [ ]. Without any lymphodepletion preconditioning, 10 days after tumor transplantation, autologous T cells were inoculated via the tail vein in a single dose [ ].
A specific antitumor activity was generated without any kind of autoimmune pathology [ ] observed in the trial [ ]. This was achieved due to the low-affinity CAR-T cells used in this preclinical model. To bypass these limitations, Chi et al. In this way, engineered T cells were able to express IL only after antigen recognition and dephosphorylation of nuclear factor of activated T cells, an inducer of IL-2 expression.
IL was found to be responsible for the effector T cell signature acting on Tbet and FoxO1 [ ]. Double-engineered CARs were able to prolong the survival of mice with long-term established orthotopic disease, together with a reduction of M2 macrophages and Tregs.
Zhang et al. The off-target toxicities were strongly reduced, but dual CARs were only able to exert antitumor activity when both antigens were expressed on the tumor cell surface [ , ]. MUC-1 is a transmembrane protein composed of a tandem repeat TR containing an external domain, bound to the membrane through non-covalent interactions with the MUCC domain, made of a short extracellular domain and transmembrane and cytoplasmic domains. The most common aberrant glycosylated form can bind the sialic acid-binding protein Siglec-9 expressed by monocytes and macrophages; after this interaction, tumor-associated macrophages TAMs increase expression of PD-L1 [ ].
Second-generation BB CAR-T cells exploiting the domains of the 5E5 antibody, which specifically recognizes the aberrantly glycosylated MUC-1, were used to treat disseminated tumor xenografts of intraperitoneally injected HsT pancreatic cells. Exploiting small molecule inhibitors and antibodies against these genes, investigators were able to restore sensitivity to CAR-T cell treatment in vitro [ ].
PSCA is undetectable in the healthy pancreas but overexpressed in PDAC, as well as in prostatic, urinary and bladder tumors, where its functions remain unclear. Moreover, preclinical experiments demonstrated that second-generation CARs, but not third-generation CARs, were able to strongly reduce subcutaneous growth of HPAC pancreatic cells, with tumor rejection in two out of five mice [ ].
To overcome the immunosuppression in the TME, Mohammed et al. The estimated primary completion date is set for February CD47 is overexpressed in leukemia and lymphoma, and in ovarian cancer, small cell lung cancer, glioma, glioblastoma and pancreatic cancer as well, where it represents a negative prognostic factor [ ].
A second-generation CD28 anti-CD47 CAR-based treatment was able to significantly decrease the volume and weight of tumors developed in mice subcutaneously injected with BxPC3 pancreatic cells [ ].
B7-H3, instead, is a member of the B7 costimulatory or co-inhibitory family delivering an immunosuppressive signal. With a limited expression in normal tissue, B7-H3 is expressed by the tumor-associated vasculature and fibroblasts, and correlates with poor prognosis and outcome [ ]. These CAR-T cells were able to cause the tumor regression growth with regard to both cell lines [ ]. These data support this tailored approach as a powerful tool for targeting solid tumors, including PDAC.
Passive immunotherapies, mainly represented by monoclonal antibodies, are efficacious in many types of cancers, and the first used in clinical practice were EGFR- or VEGF-antibodies in colorectal cancer, and trastuzumab in Herpositive breast cancer. Other targeted molecules have, so far, been unsuccessful in pancreatic cancer, such as cetuximab and bevacizumab [ ]. A promising molecule combining adaptive and innate immunity is CD40, a member of the TNF receptor family [ ].
CD40 is expressed on monocytes and DCs and also B cells, platelets and non-hematopoietic cells and tumor cells [ , ]. The significance of CD40 in tumor immunology was highlighted by a series of pioneering articles that showed that administering an agonistic antibody induced protective T cell immunity in murine cancer models of T-cell lymphoma and renal carcinoma [ , ].
CD40 agonists have been exploited to ameliorate the three immune cell cycle steps: tumor killing, T-cell immunity induction and immunosurveillance activation [ ] [Figure 1]. The most widely used agonist is the fully human CDspecific monoclonal antibody called CP, Even if CD40 targeting is effective in activating the immune system, its clinical activity is fairly limited. Therefore, it is clear that combination with other treatments is pivotal for effective translation of the CD40 agonist.
Alternatively, CD40 antibodies have been combined with IL-2 immunotherapy as a strategy to induce tumor-specific T cell immunity in tumor models of renal cell adenocarcinoma or Lewis lung carcinoma.
CD40 stimulation and IL-2 synergize to induce complete regression of metastatic tumors due to potentiation of T cell survival and CD40 expression of DCs, stimulating an immunomodulatory cascade [ ]. To understand the mechanisms of action of the anti-CD40 antibody, many studies have used a genetically engineered mouse model of pancreatic cancer [ 5 ]. Using an agonist rat anti-mouse mAb as a prototype for CP,, Beatty et al. Notably, in a second set of experiments, mice spontaneously developing pancreatic tumors treated with the anti-CD40 mAb FGK45 and gemcitabine showed a major tumor regression compared to gemcitabine alone, supporting that observed in the previous model [ ].
In addition, the same rate of tumor regression was obtained with anti-CD40 mAb alone as that produced by combination with gemcitabine. Administration of anti-CD40 in PDAC-bearing mice did not produce a significant change in the number of TAMs within the tumor, but a transitory change in macrophage activation i.
Moreover, macrophages isolated from the pancreas of tumor-bearing animals treated in vivo with anti-CD40 mAb were capable of lysing tumor cells in vitro [ ]. These findings reinforce the idea that CD40 immune therapy may be dependent on macrophages, and that the CD40 pathway can be harnessed to restore tumor immunosurveillance by targeting tumor-infiltrating macrophages. This particular study did not investigate the role of B cells and DCs, although both cells can be activated by the CD40 agonist or anti-CD40 mAb [ ].
Indeed, Schultze et al. As DCs have an enhanced capacity to take-up antigens when immature [ ] , chemotherapy followed by CD40 activation but not vice versa, elicited effective T-cell dependent immunity in tumor-bearing mice compared with anti-CD40 alone [ , ].
However, the addition of nab-paclitaxel to gemcitabine, which is more effective in patients than gemcitabine alone, synergizes to trigger tumor regression and improve survival in spontaneous PDAC mouse models [ ]. Given the preclinical success, CDtargeting agents have progressed to the clinical phases. Stromnes et al. Although there were no observed differences in tumor growth, Gr-MDSC depletion decreased ECM deposition and enhanced caspase-3 cleavage in cancer cells.
Colony-stimulating factor-1 CSF-1 acts as a monocyte attractant and is one of the main growth factors for monocyte-lineage cells. Moreover, CSF-1 induces polarization of macrophages into a tumor-promoting phenotype [ , ]. CSF-1 tyrosine kinase receptor CSF-1R , has been the focus of attention by scientists and companies who have developed a number of small molecules and antagonists to block its action [ ].
Zhu et al. In preclinical PDAC models, this combined therapy led to regression of established orthotopic tumors [ ]. Similarly, Mitchem et al. In physiological conditions, the activation of T cells is counterbalanced by inducing inhibitory stimuli to maintain immune homeostasis and to limit tissue damage and autoimmune reactions.
Signals and regulators involved in these kinds of inhibitory responses are known as immune checkpoints IC. Among the molecules responsible for the negative regulatory processes, the most studied and characterized are CTLA-4 and PD CTLA-4 competes with the co-stimulatory receptor CD28 in binding CD80 also known as B and CD86 also known as B molecules, to modulate the strength of the activated T cell responses or to enhance Treg-mediated immunosuppression [ ].
Activating IC pathways combined with the recruitment of suppressive cell populations, is a typical immune-escape mechanism adopted by different types of cancers [ , ]. We have previously demonstrated that the tumor area is infiltrated by Tregs and Th17 cells that frustrate effector T cells much more than the normal surrounding mucosa [ ]. Taking these premises into account, the use of ICIs to disrupt Treg-mediated immunosuppression and to block the inhibitory pathways on effector T cells, seems to be potentially effective in PDAC treatment [Figure 1].
The mechanism of action of ICIs is to stimulate immune-mediated recognition and elimination of the tumor. Ipilimumab is the first anti-CTLA-4 monoclonal antibody approved for treating metastatic melanoma patients [ ]. These results were also confirmed by a phase II trial NCT in which the single agent ipilimumab was tested for the treatment of locally advanced or metastatic pancreatic adenocarcinoma [Table 1]. Only one out of 27 subjects showed a significantly delayed response, suggesting that ipilimumab monotherapy is ineffective for treating advanced PDAC [ ].
Even anti-PD-1 mAbs such as pembrolizumab and nivolumab and anti-PD-L1 mAbs such as ateolizumab, durvalumab and avelumab have been approved by the FDA for treating different solid tumors [ ].
Unfortunately, opposite results were observed in a genetically engineered PDAC mouse model, in which anti-PD-L1 treatment alone was ineffective [ ]. In a study conducted by Le et al. Treatment with pembrolizumab was able to induce a complete response in two patients, a partial response in three patients and stabilization of the disease in one patient the remaining two patients could not be evaluated [ ].
The high mutation rate observed in MMR-deficient tumors, due to the failure of the DNA repair mechanisms, increases their immunogenicity and makes them suitable for checkpoint inhibitor treatments. One of the reasons for the failure of ICIs in treating pancreatic cancer may be the highly immuno-suppressive TME, which makes it comparable to an immune-privileged site [ ].
To overcome these adverse conditions, ICIs were tested in combination with treatments that have been shown to affect steps of the cancer immunity cycle that are deficient in PDAC. Briefly, upon chemotherapy, cancer cells undergo necrosis thereby releasing molecules that act as danger signals which, in turn, activate the innate immune system.
Furthermore, it has been shown that some chemotherapeutic agents can increase MHC-I expression on the surface of the cancer cells and promote maturation of DCs. Overall, chemotherapy improves the immunogenicity and antigenicity of the tumor [ ] by enhancing potential benefits from the coupling with ICIs.
In another study, Winograd et al. Gemcitabine combined with the anti-CTLA-4 antibody has been evaluated in two different phase Ib trials. Respectively, 34 and 16 patients were treated with gemcitabine with or without tremelimumab [ ] and ipilimumab [ ].
Interestingly, no patients had progressive disease [ , ]. The overall survival was 9. Many different trials with ipilimumab, avelumab, pembrolizumab, nivolumab and durvalumab are ongoing, either given alone or combined with chemotherapy and other biological drugs [ ].
As previously described for chemotherapy, radiotherapy RT can also induce ICD of cancer cells and enhance the antitumor immune response [ ]. PD-L1 blockade in association with RT significantly delayed tumor growth, which was enhanced by the addition of gemcitabine [ ]. Similarly, Victor et al. According to these findings, it was suggested that a combination based on vaccination and ICI could induce an effective anticancer response.
The median OS of patients receiving the combined treatment was 5. In patients with an OS longer than 4. Similarly to that observed in preclinical experiments, Lutz et al. The lymphocytes used for adoptive T cell therapy both autologous and allogenic T cells face the same problem deriving from TME immunosuppression described above. ACT flop is often connected to enhanced expression of the T cell inhibitory marker, namely PD-1 [ , ]. Ironically, recognition of tumor cells by transferred T cells leads to T cell activation and consequently upregulation of PD-1 on their surface; similarly, tumor cells enhance PD-L1 expression in response to T cells.
This ultimately leads to abrogation of T cell activity and thus ACT failure [ ]. The therapeutic effects correlated with an increased function of anti-Her2 T cells and a significant decrease in tumor-infiltrating MDSCs [ ]. The PDAC TME is characterized by cells exerting both anti-tumor and pro-tumor functions such as endothelial cells, fibroblasts, lymphocytes and myeloid-derived cells.
These populations are able to influence therapeutic responses and to sustain tumor progression by compromising the antitumor activities of effector cells.
TILs may encounter a suppressive environment involving inhibitory cytokines, hypoxia, as well as a dense fibrotic stroma and abnormal blood vessels that act as physical barriers preventing them from functioning properly. These interactions generate negative signals leading to immune suppression [ ].
In particular, Candido et al. In addition, macrophages can induce fibrosis, a key element of T cell exclusion from the TME [ ]. Moreover, it has been demonstrated that Tregs are able to mediate an immunosuppressive mechanism through the co-expression of CD39 and CD73 molecules on their surface.
In addition, Tregs can directly kill effector cells via perforin or granzyme release [ ]. The immunosuppressive state, responsible for the failure of most of immunotherapeutic approaches, can be directly sustained also by tumor cells. Fogar et al. Therefore, different from more immunogenic tumors such as renal cell carcinoma or melanoma, which attract tumor-infiltrating effector cells [ ] , pancreatic cancer shows poor immunogenicity, which results from both dysfunctional antitumor response and surmounting immunosuppression.
Deeper genetic characterization of solid tumors has led to the identification of specific subtypes of the same histotype tumor that benefit from different treatments. Thanks to an integrated genomic analysis of cases of pancreatic ductal adenocarcinoma, 4 different tumor subtypes were identified: squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine.
Of note, this subgroup displayed upregulated CTLA-4 and PD-1 suppressive pathways, suggesting a higher potential response to the inhibition of immune checkpoints compared to the other subtypes. However, stratification based on tumor immunological background might identify those patients who will benefit from immunotherapy strategies in general [ ]. Melanoma and non-small cell lung cancer are hot tumors with a high tumor mutation burden, making them highly antigenic and immunogenic and thus potentially more sensitive to immunotherapy [ ].
Unfortunately, PDAC, alongside a strong immunosuppression, has a low number of genomic mutations in protein coding regions. This small antigen mutational burden may be another reason for the difficulty of inducing an effective antitumor T cell response [ ]. Due to many of its intrinsic characteristics, including a well-established desmoplastic reaction and an immunosuppressive microenvironment, pancreatic cancer actually represents the dark side of immunotherapy.
Compared to other solid tumors, indeed, many immunotherapy approaches drastically fail when applied to pancreatic cancer patients. The scientific community has developed sophisticated tools to study the biology of pancreatic cancer such as Avatars, genetically engineered mice, and organoids, in which novel therapeutic drugs can be tested. Genetically engineered mouse models represent the best choice for studying antitumor immune responses and novel immunotherapy approaches, as they mimic the complex relationship between the immune system and tumor cells.
Of equal importance is the possibility to develop novel clinical studies and to enroll patients in clinical trials. The huge increase in funds focused on PDAC, together with advanced efforts by the scientific community, can provide hope for patients affected by this tumor. This work was supported by grants from Associazione Italiana Ricerca sul Cancro 5 x mille no. Cancer statistics, CA Cancer J Clin ; Projecting cancer incidence and deaths to the unexpected burden of thyroid, liver, and pancreas cancers in the United States.
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