Immunotherapy for pancreatic cancer - Future Medicine

Review For reprint orders, please contact: [email protected]

Immunotherapy for pancreatic cancer: present and future

Despite the identification of some efficient drugs for the treatment of metastatic pancreatic cancer, this tumor remains one of the most lethal cancers and is characterized by a strong resistance to therapies. Pancreatic cancer has some unique features including the presence of a microenvironment filled with immunosuppressive mediators and a dense stroma, which is both a physical barrier to drug penetration and a dynamic entity involved in immune system control. Therefore, the immune system has been hypothesized to play an important role in pancreatic cancer. Thus, therapies acting on innate or adaptive immunity are being investigated. Here, we review the literature, report the most interesting results and hypothesize future treatment directions.

Francesca Aroldi1 & Alberto Zaniboni*,1 UO Oncologia, Poliambulanza Foundation, Via Bissolati 57, 25124 Brescia, Italy *Author for correspondence: zanib@ numerica.it 1

First draft submitted: 12 December 2016; Accepted for publication: 28 April 2017; Published online: 9 June 2017 Keywords: immunotherapy • pancreatic cancer • vaccines

Despite research efforts, pancreatic cancer (PC) is still characterized by a poor prognosis, with the majority of patients presenting with advanced disease or developing metastases very early [1] . Many trials investigating new drugs or combinations of well-known drugs have failed to demonstrate benefits. This disease is often resistant to chemotherapy, radiotherapy and target therapies [2] . Nevertheless, small increases in overall survival (OS) have been reported for the use of gemcitabine alone and in association with nab-paclitaxel [3] , 5-fluorouracil–leucovorin–oxaliplatin–irinotecan (FOLFIRINOX) [4] and recently nal-iri plus 5 fluorouracil and leucovorin [5] . These findings can be explained by the immunemediating effect of gemcitabine and the advantage of nanotechnology that bypasses the dense stroma surrounding pancreatic tumor cells with nab-paclitaxel and nal-iri. A fascinating hypothesis concerns the mode of action of gemcitabine and FOLFIRINOX; the first allows antigen cross-presentation by dendritic cells, increasing the T-cell response

10.2217/imt-2016-0142 © 2017 Future Medicine Ltd

and reducing suppressor cell infiltration; the second is often administered with cellular growth factors that may induce an immune response [4] . Given the scarcity of effective drugs available for PC treatment and the possibility that those are efficient because of activate immune system (IS), the investigation of immunotherapy is especially important in PC research. We summarize the current knowledge about immunotherapy for PC and hypothesize about the future treatment landscape. The immune response in PC The ability of the IS to counter tumor development and progression has been reported for many cancers, including PC. This issue has been studied since the beginning of the 20th century, first by Ehrlich and later by Burnet and Thomas. The latter proposed the immune surveillance theory, according to which the IS can prevent cancer by recognizing and eliminating nascent malignant cells. More recently, immunosurveillance

Immunotherapy (2017) 9(7), 607–616

part of

ISSN 1750-743X

607

Review Aroldi & Zaniboni has been evaluated as a part of cancer immunoediting, which considers carcinogenesis as a dynamic process divided into three steps: elimination, equilibrium and escape. During the first phase, the IS destroys the cancer cells before clinical presentation; during the second phase, the proliferation of resistant clones with decreased immunogenicity leads to an equilibrium between the suppression of tumor cells and the growth of the resistant cells. When this balance is disrupted, the escape phase occurs and cancer develops. An infiltration of immune suppressor cells without immune effector cells has been observed in preinvasive pancreatic lesions, illustrating the importance of the IS in PC. Pancreatic tumor cells express many antigens (Ag) that are able to generate B- and T-cell responses, with the most frequent Ag being Wilm’s tumor gene 1 (WT1), mucin 1 (MUC1), human telomerase reverse transcriptase, mutated KRAS and carcinoembryonic antigen. T cells can be activated by the recognition of tumor-associated Ag or tumor-specific Ag, but to mount an efficient immune response, both reduced inhibitory signals and positive costimulatory molecules are required [6] . Some components of the IS can play dual roles of immunostimulation and immunosuppression. Within the adaptive IS, CD8 + cytotoxic T cells and Th17 cells have been associated with both favorable and poor prognoses [7,8] . On one hand, CD4 + Th1 cells have been associated with antitumor actions; on the other hand, CD4 + Th2 cells and Tregs have been linked to cancer-promoting features [9–11] . Within the innate IS, M1 macrophages may sustain antitumor responses, whereas M2 macrophages may be involved in tumor promotion. The role of dendritic cells is also controversial, because mediating T-cell actions are correlated with favorable outcomes but can also facilitate a shift from Th1 to Th2 response [12] . Immunotherapy Immunotherapy treatments are divided into active treatments, such as vaccines, and passive treatments, such as monoclonal antibodies. Active treatments can be specific (i.e., adaptive T cells) or nonspecific (i.e., cytokines) [13] . Treatments can also be subdivided into modulators of adaptive immunity, modulators of innate immunity, vaccines and adoptive transfer [14] . Many studies have been conducted or are ongoing to assess the efficacy of this approach (Table 1) .

The aim of cancer vaccines is to prevent cancer development or to eliminate existing tumors by stimulating tumor-specific T cells. Four subtypes of vaccines have been identified: protein, peptide-based, cell-based and genetic vaccines. The first two subtypes are composed of tumor-associated Ag and are less powerful [35] ; the third subtype can be based on autologous or allogeneic immune or cancer cell mixtures that are isolated from the patient, activated and reinfused into the patient [35] ; the fourth subtype includes DNA, RNA and viruses transfected into dendritic or somatic cells [35] . Cell-based vaccines

Algenpantucel-L is a cell-based vaccine comprising two irradiated human PC cell lines (HAPa-1 and HAPa-2) transmuted to express the murine enzyme α-1,3-galactosyl transferase [36] ; antibodies against this enzyme have been found in human blood. The goal is the destruction of α-1,3-galactosyl transferase expressing cells via the interaction between ligands and antibodies. Based on the promising Phase II trial results [37] , a Phase III study is in progress to assess the therapeutic capacity of this drug both in resected PC patients [38] and patients with borderline resectable or unresectable locally advanced disease [39] . Another interesting type of vaccines is GVAX vaccines, which are based on irradiated cells transfected with a GM-CSF vector; GVAX vaccines have been studied in many types of cancers including PC. The results of a Phase I trial suggested that this vaccine can override immunosuppression; in the responsive patients, circulating CD8 + T cells have been detected postvaccination whereas were absent prevaccination. GVAX vaccines have been investigated in combination with chemoradiotherapy (5-fluorouracil) in resected PC patients in a Phase II trial, with a promising outcome: 1-year OS in 85% of the patients and 1-year disease-free survival in 67.4% of the patients, with a median OS of 24.8 months and median disease-free survival of 17.3 months [40] . The only currently approved vaccine is sipuleucel-T, an immunotherapy designed to stimulate IS through dendritic cells that is effective in metastatic prostate cancer patients [41] . The use of these cells can be promising because they stimulate an immune response by transporting Ag. Phase I studies are testing dendritic cells pulsed with MUC1 [42] or stem cells [43] , but further research is necessary to determine the impact on OS.

Active or adaptive immunotherapy (vaccines)

Active immunotherapy is characterized by the administration of the tumor antigens to developed an immune response and immunologic memory. Vaccines are the most representative examples.

608

Immunotherapy (2017) 9(7)

Protein/peptide/genetic vaccines

Protein–peptide vaccines are being investigated in several clinical trials, but most of these trials are currently in Phase I; some protein–peptide vaccines are directed

future science group

Immunotherapy for pancreatic cancer

Review

Table 1. The majority of immunotherapy clinical trials conducted. Categories

Combined with

Setting

Clinical outcome

Immune checkpoint CTLA4 [15] inhibitor CTLA4 [16] CD40 [17]

Target

GVAX None Gemcitabine

Unresectable or metastatic Unresected and metastatic Unresected and metastatic

↑1-year OS by 20% compared with GVAX alone 1 patient delayed regression of hepatic metastases ↑mOS by 1.7 months vs gemcitabine alone, 1 patient had complete resolution of hepatic metastases

Allogeneic

GM-CSF [18] GM-CSF [19]

5-FU Cyclophosphamide

Adjuvant Metastatic

↑OS (53–76%) No benefit

Autologous: DC

MUC1 [20] MUC1 [21] MUC1 [22] MUC1 [23] MUC1 [24]

Gemcitabine None None None None

Metastatic Resected and unresectable Metastatic Metastatic Resected

2 CR, 5 PR, 10 SD mOS of 9 months 1 patient had remission, 5 had stable disease. OS 9.8 months 30% OS, 4 years No benefit

Vaccines

Gastrin-17 [25] Gastrin-17 [26] Hedgehog [27] GVAX [28] MUC1 [29] WT1 [30] Trop-2 [31] Telomerase [32] Telomerase [33] KRAS [34]

None None Gemcitabine Cyclophosphamide Incomplete Freund’s Gemcitabine None Gemcitabine GM-CSF None

Metastatic Metastatic Metastatic Metastatic Metastatic Unresectable Metastatic Metastatic Metastatic Adjuvant

↑OS (4–7.2 months) ↑OS by 54% OS 10 months ↑OS (4–6.2 months) No benefit ↑mOS by 7 months (p < 0.01) No benefit No benefit OS of 4.3 months (p < 0.01) ↑OS (2–5.4 months) 1-year OS 20%

↑: Increase; 5-FU: 5-Fluorouracil; CR: Complete response; CTLA4: Cytotoxic T-lymphocyte-associated protein 4; mOS: Median overall survival; MUC-1: Mucin 1; OS: Overall survival; PR: Partial response.

against KRAS [44] and WT1 in association with gemcitabine [45] and KIF20A peptide [46] , but further studies are needed to understand the application of these vaccines. A recent Phase III trial tested GV1001, a vaccine targeting human telomerase reverse transcriptase subunit in patients affected by locally advanced or metastatic PC in combination with gemcitabine and capecitabine [47] . Although this vaccine failed to produce an improvement in OS, it has improved patients’ clinical condition. Another vaccine that has produced interesting results is Gastroimmune. This vaccine is composed of an amino terminal sequence of gastrin-17 (G17) and diphtheria toxoid (DT). In a Phase III trial, Gastroimmune did not show a survival benefit in all patients but increased OS in antibody responders [48] . Most of the genetic vaccines are in early phases of study, and the results are currently unsatisfying but could be promising in the future. Bacteria

The use of microbes has received particular attention. Microbes induce acute inflammation and may induce immune memory and immunosurveillance. The most


studied bacteria are Listeria monocytogenes and Mycobacterium obuense. Treatments using L. monocytogenes exist in two formulations: live-attenuated bacteria expressing mesothelin (CRS-207) and radioactivelabeled bacteria. M. obuense has been investigated in clinical studies, but efficacy has only been reported in preclinical models [49] . In a Phase II trial, a combination of low-dose cyclophosphamide, GVAX and CRS207 vaccines were compared with low-dose cyclophosphamide and GVAX only in previously treated metastatic PC patients, and increased OS (9.7 vs 4.6 months) was reported in those who received at least three doses of CRS-207 combined therapy [50] . Two studies are currently investigating CRS-207 in combination with checkpoint inhibitors in metastatic PC patients; one study is assessing a combination with anti-programmed death-1 (anti-PD1) antibodies [51] and the other is assessing a combination with anticytotoxic T-lymphocyte-associated protein 4 (antiCTLA4) antibodies plus GVAX in patients previously exposed to FOLFIRINOX [52] . In contrast to L. monocytogenes, IMM-101, a formulation of heat-killed M. obuense, does not act as

www.futuremedicine.com

609

Review Aroldi & Zaniboni a vehicle, but holds a variety of Ag active in IS, particularly memory CD8 + cells, and increases the secretion of perforin and granzyme B at tumor sites [53] . In a Phase II trial, the combination with gemcitabine was compared with gemcitabine alone in patients affected by metastatic or locally advanced PC, and the combination demonstrated a small advantage in OS (6.7 vs 5.6 months) in metastatic patients (7.0 vs 4 months) [54] . Passive or adaptive immunotherapy

In passive or adaptive immunotherapy, compounds such as monoclonal antibodies or cell types are given to patients to induce an immune response, but the effect is not long-lived. The advantage of these therapies is that specifically interesting targets may promote the development of an antigen-specific immune response [55] . In particular, the inhibition of the immune checkpoint molecules PD1 and CTLA4 has been studied. Ipilimumab, a monoclonal antibody acting on the CTLA4 receptor failed to demonstrate efficacy in advanced PC patients [56] . However, an increased OS (5.7 vs 3.6 months) was reported for the combination of ipilimumab and GVAX in comparison with ipilimumab monotherapy in a Phase Ib study [57] . Thus, this type of treatment appears to be ineffective in monotherapy but potentially ineffective in association with vaccines or chemotherapy. Therefore, several studies are assessing the activity of combined treatments including radiochemotherapy. Unfortunately, the inhibition of PD1 and programmed death-1 ligand (PDL1) does not correlate with an increased OS in PC patients. However, some benefits have been reported for the use of MEDI4736 anti-PDL1 in an interim analysis of a Phase II trial [58] . Given that immune checkpoint inhibitors alone have not produced satisfying results, the association with anti-CTLA4 and PDL1/PD1 is under investigation. Modulators of adaptive immunity

Modulators of adaptive immunity include the immune checkpoint inhibitors discussed previously and IL-15 superagonist, TGFβ, indoleamine 2,3-dioxygenase (IDO), IL-10 inhibitors. IL-15 is a cytokine secreted by macrophages and some other cells following viral infection. This cytokine induces NK and T-cell proliferation. In preclinical models, the production of IL-15 was found to eradicate pancreatic tumors [14] . In a Phase I trial, the IL-15 superagonist ALT-803 demonstrated safety in advanced PC patients and was associated with increased memory CD8 lymphocytes, T cells and NK [14] . TGFβ is another cytokine involved in the

610


differentiation, chemotaxis, proliferation and activation of many immune cells. The role of TGFβ is controversial, because although its activation leads to immunosuppression, which promotes cancer development, it also leads to a reduction in tumor growth [59] . IDO through tryptophan catabolism blocks T-cell activity, thereby promoting a microenvironment favorable to cancer. IDO also fosters resistance to immunotherapy. Therefore, a clinical trial is ongoing to assess the activity of IDO inhibition combined with nab-paclitaxel plus gemcitabine in metastatic PC [60] . The use of IL-10 in PC treatment is currently being investigated; this molecule has immunosuppressive activity [61] . Modulators of innate immunity

Innate immunity is the first barrier against pathogenic microorganisms and the first step in developing an effective immunity response. Many studies have been performed to identify a possible role of modulators of innate immunity in PC therapy. CD40 is a costimulatory protein that is necessary for the activation of T lymphocytes; the efficacy of CD40 agonist was evaluated in a Phase I trial in metastatic PC, with partial responses reported in almost 20% of patients [62] . A Phase II study has been planned. Other agents examined for the treatment of metastatic PC include tolllike receptor agonists, Bruton’s tyrosine kinase, inhibition of myeloid-derived suppressor cells’ chemotaxis, Janus kinase inhibition, and vitamin D analog; unfortunately, studies of these agents have not reported remarkable results [14] . T-cell-based adoptive cell transfer Adoptive cell transfer consists of sampling T cells from the patient, followed by expansion of these cells and re-administration to the patient [63] . The hypothesis is that by overcoming the immune tolerance state, an efficient adaptive immune response against the tumor can be generated. Two types of treatment are possible: in one type of treatment, the isolated T cells are tumorinfiltrating lymphocytes, whereas in the other type of treatment, T cells expressing particular receptors are detected, activated and reinfused [63] . Receptors can also be engineered by associating an antibody portion with a T-cell receptor; these receptors are called chimeric antigen receptors [63] . In this setting, the cytokine-induced killer cell has been the most widely tested achieving interesting results. In a Phase II trial, the association with gemcitabine has reported an OS of 26.6 weeks with an improvement in quality of life [64] . Although still immature, the use of KRAS-specific tumor-infiltrating lymphocytes transferral seems to be fascinating [65] .



The peculiarity of PC

PC has unusual features that make it resistant to treatment. A successful strategy to fight this cancer has not been established yet. There are many possible explanations for the resistance to treatment: • There is a high representation of immunosuppressive leukocytes in the cancer microenvironment [66] . • Intratumoral effector T-cell levels are lower than in other tumors [67] . • There is immune privilege in the microenvironment, developed through an inflammatory program determined by the RAS oncogene [68] .

Review

• A strong desmoplastic reaction of fibroblastic and cancer cells, PDGF, fibronectin and proteoglycans forms a physical barrier against drug penetration [69] . • There is protumor stroma cell activity. The important role of the microenvironment in immunosuppression is already known. Despite the presence of T cells, the recruitment of suppressor cells leads to the inactivation of IS. This inactivation may explain the inefficacy of immunotherapy and strengthens the hypothesis that several drugs belonging to the same or a different class should be used in combination. Some drugs can interact synergistically; the results of combined treatment studies have demonstrated better

Table 2. The most important trial discussed in the text. Drug name

Phase Drug composition

Combined with

Setting

Outcome

Algenpantucel-L

II

HAPa-1, HAPa-2 expressing α-GT

None

Adjuvant

1 y DFS 62% 1y OS 86%

GVAX [40]

II

Irradiated cells transfected with a GM-CSF

Chemoradiation

Adjuvant

1y DFS 67.4% 1y OS 85%

[42]

I

MUC1-peptide-pulsed dendritic cells

None

Metastatic

No toxicity grades 3–4

[45]

I

WT1 peptide-based cancer vaccine

Gemcitabine

Metastatic

1y OS 29%

[46]

I

KIF20A-derived peptide

Gemcitabine

Metastatic

1y OS 11.1%

GV1001 [47]

III

hTERT subunit

Gemcitabine + capecitabine with Locally sequential GV1001 vs advanced concurrent GV1001 or gemcitabine Metastatic alone

No OS improvement with GV1001 Better performance status

Gastroimmune [48]

III

G17DT

None

Metastatic

Anti-G17DT responses 1y OS 73.8%

CRS-207 [50]

II

Live-attenuated Listeria monocytogenes expressing mesothelin

Low-dose cyclophosphamide,+ GVAX vs low-dose cyclophosphamide,+ GVAX + CRS + 207

Metastatic

OS 4.6 vs 9.7 months

IMM-101 [54]

II

Heat-killed Mycobacterium obuense

Gemcitabine vs gemcitabine + IMM-101

Locally advanced metastatic


Ipilimumab [56]

II

Anti-CTLA4

None

Locally advanced metastatic

Improvement of performance status

Ipilimumab [57]

Ib

Anti-CTLA4

Ipilimumab + GVAX vs ipilimumab

Metastatic


CP-870,893 [62]

I

CD40 agonist

Gemcitabine

Metastatic

Partial responses in 20% of patients

[64]

II

CIK cell

Gemcitabine

Metastatic

OS 6.5 months

[37]

1y OS: 1-Year overall survival; 1y DFS: 1-Year disease-free survival; α-GT: α-1,3-Galactosyl transferase; CIK: Cytokine-induced killer; CRS-207: Live-attenuated expressing mesothelin; CTLA4: Cytotoxic T-lymphocyte-associated protein 4; DT: Diphtheria toxoid; G17: Gastrin-17; hTERT: Human telomerase reverse transcriptase; MUC1: Mucin 1; WT1: Wilm’s tumor gene 1.



611

Review Aroldi & Zaniboni results in comparison with the monotherapy (Table 2) . As discussed above, some innate immunity cells can perform different roles in reaction to tumors. In particular, during cancer development, tissue-resident macrophages are substituted with monocytes that then turn into tumor-associated macrophages, which can differentiate into M1 or M2 depending on how they are stimulated. Treatments, such as CD40 agonists and radiation, which promote the switch to the M1 subset, seem to better control tumor growth [70] . Other protagonists of immune control are the myeloid-derived suppressor cells that as myeloid progenitors can generate dendritic cells, macrophages and granulocytes, which inhibit T-cell activity, releasing molecules such as reactive oxygen species and tumor derived cytokines. One of the first steps in PC carcinogenesis is the mutation of KRAS, which characterizes almost 90% of PC. Collins et al. explain this phenomenon with the KRAS effect on the microenvironment [68] . This phenomenon seems to be particularly involved in inflammation, the Hedgehog pathway, and communication between epithelial cells and the microenvironment, maintaining a fibroinflammatory stroma [66] . Unfortunately, drugs targeting KRAS are inefficient. PC is surrounded by dense stroma characterized by a desmoplastic reaction that can be an obstacle to drug penetration, but that can also secrete immunosuppressive mediators. Pancreatic stellate cells can be identified inside the stroma and can switch to fibroblasts that release factors that improve tumor proliferation and chemoresistance. Moreover, this mechanism seems to be self-maintained because secreted molecules from tumor cells stimulate cancer stroma [71] . Targeting this mechanism has proven to be a good strategy; the combined action of CTLA4 inhibition and loss of myofibroblasts increases OS more than immunotherapy alone, suggesting a synergistic interaction and a promising field of study [72] . There is also a subpopulation of stromal cells, which express the FAP and are responsible for protumor effects; the modulation of these effects is still being studied [70] . The vitamin D agonists are under investigation for this purpose [14] . Conclusion The backbone of PC treatment is still chemotherapy, but an interesting hypothesis suggests that the efficacy of chemotherapy may be at least partially related to an immunological effect. As in other cancers, the use of immunotherapy has been investigated in PC treatment, but almost exclusively in Phase I or II trials. In PC, many mechanisms and immunological balances underlie tumor development, growth and maintenance; therefore, the inhibition of one pathway

612


is unlikely to lead to cancer regression. Therefore, although some interesting results have been reported for combined therapies, it is premature to define their application as a practice-changing approach. Immunotherapy is a promising field, but despite its fast development, there are still many unknowns. Future perspective Like several other cancers, PC is considered to be a heterogeneous disease. PC can be divided in two principal categories: immunogenic and nonimmunogenic, defined by immunoscore [73] that is based on the determination of intratumoral density of two lymphocyte populations (CD3 +/CD45RO +, CD3 +/CD8 + or CD8 +/CD45RO +) in the tumor and its invasion front. These categories may have consequences for therapeutic strategies. Given that the first category is characterized by an inflammatory microenvironment, the use of immune checkpoint inhibitors and immune adaptive modulators can be useful. In contrast, in the second category, vaccines and adoptive cell transfer seem to be better treatment options. The use of chemotherapy and radiotherapy can be evaluated in both of categories. As discussed previously, the most attractive strategy is the combination of additional drugs belonging to the same or a different class such as the combination of adaptive immune modulators with vaccines. Activating the IS first can provide the basis for effective vaccine activity. The immune checkpoint inhibitors can have synergistic interactions with other immune checkpoint inhibitors and with chemotherapy and modulators of innate immunity but have failed to demonstrate efficacy alone. Moreover, radiotherapy has an effect on the IS, and may enhance MHC class I expression and increase the expression of cellular death receptors, such as FAS/ CD95, TRAIL [74] . So the development of a combined therapy with innate and adoptive modulators should be encouraged. As previously discussed, the stroma is a dynamic entity that is important for PC maintenance, so targeting stroma compounds can produce beneficial results in association with immune modulators but not in monotherapy. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.



Review

Executive summary Cell-based vaccine • This can be based on autologous or allogeneic immune or cancer cell mixtures isolated from patients, activated and reinfused to patients. • Algenpantucel-L and GVAX have achieved promising results in Phase II trials in adjuvant setting.

Protein/peptide/genetic vaccines • Among the four subtypes of vaccines – protein, peptide-based, cell-based and genetic vaccines – the first two are composed by tumor-associated Ag whereas the latter include DNA, RNA, virus transfected to dendritic or somatic cells. Both of them are less powerful.

Bacteria • These produce an acute inflammation; they may induce immune memory and immunosurveillance. The most studied bacteria are the Listeria monocytogenes (CRS-207) and theMycobacterium obuense (IMM-101). • In metastatic pancreatic cancer (PC) patients, the first has obtained an improvement of overall survival in combination with chemotherapy, instead the second has demonstrated only a little advantage.

Inhibition of immune check point • This type of treatment appears to be ineffective in monotherapy but the association with vaccines or chemotherapy has reported better results. Therefore, many trials are testing the activity of combined treatments including radiochemotherapy.

Modulators of adaptive immunity • Modulators of adaptive immunity include not only the immune checkpoint inhibitors, but also IL-15 superagonist, TGFβ, indoleamine 2,3-dioxygenase and IL-10 inhibitors. We have only a few data from preclinical and Phase I studies but many trials are ongoing.

Modulators of innate immunity • CD40 agonist has achieved a little activity in a Phase I trial in metastatic PC patients. • Other agents examined for the treatment of metastatic PC include toll-like receptor agonists, Bruton’s tyrosine kinase, inhibition of myeloid-derived suppressor cells chemotaxis, Janus kinase inhibition and vitamin D analog, but unfortunately without reporting remarkable results.

Adoptive cell transfer • This treatment consists in sampling of T cells from patient, expansion and readministration to him. • Interesting results are collected with the adoptive cell transfer use. 7

Carrato A, Falcone A, Ducreux M et al. A systematic review of the burden of pancreatic cancer in Europe: real-world impact on survival, quality of life and costs. J. Gastrointest Cancer. 46, 201–211 (2015).

Niccolai E, Taddei A, Ricci F et al. Intra-tumoral IFNγ-producing Th22 cells correlate with TNM staging and the worst outcomes in pancreatic cancer. Clin. Sci. 130(4), 247–58 (2016).

8

Aroldi F, Bertocchi P, Rosso E, Prochilo T, Zaniboni A. Pancreatic cancer: promises and failures of target therapies. Rev. Recent Clin. Trials 11(1), 33–38 (2016).

Wörmann SM, Diakopoulos KN, Lesina M, Algül H. The immune network in pancreatic cancer development and progression. Oncogene 33(23), 2956–2967 (2014).

9

Goldstein D, El Maraghi RH, Hammel P et al. Updated survival from a randomized Phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas. J. Clin. Oncol. 32, 1739 (2014).

De Monte L, Reni M, Tassi E et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J. Exp. Med. 208(3), 469–478 (2011).

10

Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12(4), 298–306 (2012).

11

Amedei A, Niccolai E, Benagiano M et al. Exvivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO-specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions. Cancer Immunol. Immunother. 62(7), 1249–1260 (2013).

References Papers of special note have beenhighlighted as: • of interest 1

2

3

4

Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364(19), 1817–1825 (2011).

5

Wang-Gillam A, Li CP, Bodoky G et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, Phase III trial. Lancet 387, 545–557 (2016).

12

Gao J, Bernatchez C, Sharma P, Radvanyi LG, Hwu P. Advances in the development of cancer immunotherapies. Trends Immunol. 34(2), 90–98 (2013).

Yang M, Ma C, Liu S et al. HIF-dependent induction of adenosine receptor A2b skews human dendritic cells to a Th2-stimulating phenotype under hypoxia. Immunol. Cell Biol. 88(2), 165–171 (2010).

13

Brunet LR, Hagemann T, Andrew G, Mudan S, Marabelle A. Have lessons from past failures brought us closer to the

6



613

Review Aroldi & Zaniboni success of immunotherapy in metastatic pancreatic cancer?. Oncoimmunology 5(4), e1112942 (2015). 14

Delitto D, Wallet SM, Hughes SJ. Targeting tumor tolerance: a new hope for pancreatic cancer therapy? Pharmacol. Ther. 166, 9–29 (2016).

15

Le DT, Lutz E, Uram JN et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J. Immunother. 36(7), 382–389 2013).

16

Royal RE, Levy C, Turner K et al. Phase II trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33(8), 828–833 (2010).

17

Beatty GL, Chiorean EG, Fishman MP et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331(6024), 1612–1616 (2011).

18

Lutz E, Yeo CJ, Lillemoe KD et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann. Surg. 253(2), 328–335 (2011).

19

Laheru D, Lutz E, Burke J et al. Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin. Cancer Res. 14(5), 1455–1463 (2008).

20

Kimura Y, Tsukada J, Tomoda T et al. Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma. Pancreas 41(2), 195–205 (2012).

21

Nakamura M, Wada J, Suzuki H, Tanaka M, Katano M, Morisaki T. Long-term outcome of immunotherapy for patients with refractory pancreatic cancer. Anticancer Res. 29(3), 831–836 (2009).

22

Kondo H, Hazama S, Kawaoka T et al. Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes. Anticancer Res. 28(1B), 379–387 (2008).

23

Lepisto AJ, Moser AJ, Zeh H et al. A Phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther. 6(B), 955–964 (2008).

24

614

Pecher G, Haring A, Kaiser L, Thiel E. Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a Phase I/ II clinical trial. Cancer Immunol. Immunother. 51(11–12), 669–9673 (2002).

25

Brett BT, Smith SC, Bouvier CV et al. Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer. J. Clin. Oncol. 20(20), 4225–4231 (2002).

26

Gilliam AD, Broome P, Topuzov EG et al. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. Pancreas 41(3), 374–379 (2012).


27

Jesus-Acosta A, O’Dwyer P, Ramanathan R et al. A Phase II study of vismodegib, a hedgehog (Hh) pathway inhibitor, combined with gemcitabine and nab-paclitaxel (nab-P) in patients (pts) with untreated metastatic pancreatic ductal adenocarcinoma (PDA). J. Clin. Oncol 32(Suppl. 3), Abstract 257 (2014).

28

Le DT, Wang-Gillam A, Picozzi V et al. Safety and survival with GVAX pancreas prime and Listeria monocytogenes expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J. Clin. Oncol. 33(12), 1325–1333 (2015).

29

Yamamoto K, Ueno T, Kawaoka T et al. MUC1 peptide vaccination in patients with advanced pancreas or biliary tract cancer. Anticancer Res. 25(5), 3575–3579 (2005).

30

Nishida S, Koido S, Takeda Y et al. Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. J. Immunother. 37(2), 105–110 (2014).

31

Starodub A, Ocean A, Shah M et al. SN-38 antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, as a novel platform for the therapy of diverse metastatic solid cancers: Initial clinical results. J. Clin. Oncol. 32(5s), Abstract 3032 (2014).

32

Buanes T, Maurel J, Liauw W, Hebbar M, Nemunaitis J. A randomized Phase III study of gemcitabine (G) versus GV1001 in sequential combination with G in patients with unresectable and metastatic pancreatic cancer (PC). J. Clin. Oncol. 27(15s), Abstract 4601 (2009).

33

Bernhardt SL, Gjertsen MK, Trachsel S et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating Phase I/II study. Br. J. Cancer 95(11), 1474–1482 (2006).

34

Gjertsen MK, Buanes T, Rosseland AR et al. Intradermal ras peptide vaccination with granulocyte-macrophage colony stimulating factor as adjuvant: clinical and immunological responses in patients with pancreatic adenocarcinoma. Int. J. Cancer 92(3), 441–450 (2001).

35

Guo C1, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, Wang XY. Therapeutic cancer vaccines: past, present, and future. Adv. Cancer Res. 119, 421–475 (2013).

36

Oyasiji T, Ma WW. Novel adjuvant therapies for pancreatic adenocarcinoma. J. Gastrointest. Oncol. 6(4), 430–435 (2015).

37

Hardacre JM, Mulcahy M, Small W et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a Phase II study. J. Gastrointest. Surg. 17(1), 94–100 (2013).

38

Clinical.Trials.gov identifier NCT01072981

39

Clinical.Trials.gov identifier NCT01836432

40

Lutz E, Yeo CJ, Lillemoe KD et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann. Surg. 253(2), 328–335 (2011).

41

Cheever MA, Higano CS. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin. Cancer Res. 17(11), 3520–3526 (2011).



42

Rong Y, Qin X, Jin D et al. A Phase I pilot trial of MUC1peptide-pulsed dendritic cells in the treatment of advanced pancreatic cancer. Clin. Exp. Med. 12(3), 173–180 (2012)

43

Lin M, Yuan YY, Liu SP et al. Prospective study of the safety and efficacy of a pancreatic cancer stem cell vaccine. J. Cancer Res. Clin Oncol. 141(10), 1827–1833 (2015).

44

Abou-Alfa GK, Chapman PB, Feilchenfeldt J et al. Targeting mutated K-ras in pancreatic adenocarcinoma using an adjuvant vaccine. Am. J. Clin. Oncol. 34(3), 321–325 (2011).

45

Nishida S, Koido S, Takeda Y et al. Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. J. Immunother. 37(2), 105–114 (2014).

46

Suzuki N, Hazama S, Ueno T et al. A Phase I clinical trial of vaccination with KIF20A-derived peptide in combination with gemcitabine for patients with advanced pancreatic cancer. J. Immunother. 37(1), 36–42 (2014).

47

Middleton G, Silcocks P, Cox T et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, Phase III trial. Lancet Oncol. 15, 829–840 (2014).

•

Interesting because it is a Phase III trial.

48

Gilliam A, Broome P, Topuzov E et al. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. Pancreas 41, 374–379 (2012).

metastatic pancreatic adenocarcinoma. J Immunother. 33(8), 828–833 (2010). 57

Le DT, Lutz E, Uram JN et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J. Immunother. 36(7), 382–389 (2013).

58

Segal NH, Antonia SJ, Brahmer JR et al. Preliminary data from a multi-arm expansion study of MEDI4736, an antiPD-L1 antibody. ASCO Annual Meeting Proceedings. 32(15 Suppl.) (2014).

59

Massagué J, Xi Q. TGF-β control of stem cell differentiation genes. FEBS Lett. 586(14), 1953–1958 (2012).

60

Bahary N. Results of the Phase Ib portion of a Phase I/II trial of the indoleamine 2, 3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreatic cancer. ASCO Annual Meeting Proceedings. 34(4 Suppl.) (2016).

61

Oft M. IL-10: master switch from tumor-promoting inflammation to antitumor immunity. Cancer Immunol. Res. 2(3), 194–199 (2014).

62

Beatty GL, Torigian DA, Chiorean EG et al. A Phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin. Cancer Res. 19, 6286–6295 (2013).

63

Harris TJ, Drake CG. Primer on tumor immunology and cancer immunotherapy. J. Immunother. Cancer 1, 12 (2013).

•

Interesting because it is a Phase III trial.

64

49

Quispe TW, Chandra D, Jahangir A et al. Nontoxic radioactive Listeria(at) is a highly effective therapy against metastatic pancreatic cancer. Proc. Natl Acad. Sci. USA 110(21), 8668–8673 (2013).

Chung MJ, Park JY, Bang S, Park SW, Song SY. Phase II clinical trial of ex vivo-expanded cytokine-induced killer cells therapy in advanced pancreatic cancer. Cancer Immunol. Immunother. 63(9), 939–946 (2014).

65

Tran E, Robbins PF, Lu YC. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375(23), 2255–2262 (2016).

66

Fridman WH, Dieu-Nosjean MC, Pagès F et al. The immune microenvironment of human tumors: general significance and clinical impact. Cancer Microenviron. 6(2), 117–122 (2013).

50

Dung T, Gillam A, Picozzi V et al. Safety and SURVIVAL With GVAX pancreas prime and Listeria monocytogenesexpressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J. Clin. Oncol. 33(12), 1325–1333 (2015).

51

GVAX pancreas vaccine (with CY) and CRS-207 with or without nivolumab. NCT02243371

67

52

A Phase II, multicenter study of FOLFIRINOX followed by ipilimumab with allogenic GM-CSF transfected pancreatic tumor vaccine in the treatment of metastatic pancreatic cancer. NCT01896869

Ino Y, Yamazaki-Itoh R, Shimada K et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br. J. Cancer 108(4), 914–923 (2013).

68

Passero FC Jr, Saif MW. Advancements in the management of pancreatic cancer: 2015 ASCO Gastrointestinal Cancers Symposium (San Francisco, CA, USA, January 15–17, 2015). JOP 16(2), 99–103 (2015).

Collins MA, Bednar F, Zhang Y, Brisset JC, Galbán S, Galbán CJ et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J. Clin. Invest. 122(2), 639–653 (2012).

69

Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin. Cancer Res. 18(16), 4266–4276 (2012).

70

Klug F, Prakash H, Huber PE et al. Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 24(5), 589–602 (2013).

71

Erkan M, Hausmann S, Michalski CW et al. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat. Rev. Gastroenterol. Hepatol. 9(8), 454–467 (2012).

53

54

55

56

Dalgleish AG, Stebbing J, Adamson DJ et al. Randomised, open-label, Phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer. Br. J. Cancer 115(9), e16 (2016). Monjazeb AM, Hsiao HH, Sckisel GD, Murphy WJ. The role of antigen-specific and non-specific immunotherapy in the treatment of cancer. J. Immunotoxicol. 9(3), 248–258 (2012). Royal RE, Levy C, Turner K et al. Phase II trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or


Review


615

Review Aroldi & Zaniboni

616

72

Feig C, Jones JO, Kraman M et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110(50), 20212–20217 (2013).

73

Galon J, Bindea G, Mlecnik B et al. Intratumoral immune microenvironment and survival: the immunoscore. Med. Sci. (Paris) 30(4), 439–444 (2014).


74

Vatner RE, Cooper BT, Vanpouille-Box C, Demaria S, Formenti SC. Combinations of immunotherapy and radiation in cancer therapy. Front. Oncol. 4, 325 (2014).
