Open Access

From bench to bedside a comprehensive review of pancreatic cancer immunotherapy

  • Paul R. Kunk1,
  • Todd W. Bauer2,
  • Craig L. Slingluff3 and
  • Osama E. Rahma1Email author
Journal for ImmunoTherapy of Cancer20164:14

https://doi.org/10.1186/s40425-016-0119-z

Received: 22 October 2015

Accepted: 16 February 2016

Published: 15 March 2016

Abstract

The incidence of pancreatic cancer has been increasing while its 5-year survival rate has not changed in decades. In the era of personalized medicine, immunotherapy has emerged as a promising treatment modality in a variety of malignancies, including pancreatic cancer. This review will discuss the unique pancreatic tumor microenvironment, including the cells and receptors that transform the pancreas from its normal architecture into a complex mix of suppressor immune cells and dense extracellular matrix that allows for the unrestricted growth of cancer cells. Next, we will highlight the recently completed immunotherapy clinical trials in pancreatic cancer. Finally, we will explore the on-going immunotherapy clinical trials and future directions of this engaging and changing field.

Keywords

Pancreatic cancer Immunotherapy Cancer vaccine Immune checkpoint Tumor Immunology

Background

Despite intensive research efforts to better understand its tumor microenvironment, the prognosis of pancreatic cancer remains dismal [1, 2]. The Pancreatic Cancer Action Network estimates that deaths from pancreatic cancer will be second only to lung cancer by 2020 [3]. Accordingly, novel treatment strategies for pancreatic cancer are desperately needed.

Immunotherapy is one of these novel strategies that has been under investigation in a variety of cancers. This review will focus on pancreatic cancer from an immune perspective, describing its immune microenvironment and the completed and ongoing clinical trials in this area.

Review

Pancreatic cancer from an immune perspective

Pancreatic cancer is unique from an immunological perspective. First, intratumoral effector T-cells are rare, in contrast to many other solid tumors for which infiltration of effector T-cells is often prominent [4, 5]. Second, the RAS oncogene drives an inflammatory program that establishes immune privilege in the pancreatic tumor microenvironment (PTME) [6]. Third, pancreatic cancer is associated with a massive infiltration of immunosuppressive leukocytes into the tumor microenvironment [4, 5]. Fourth, the development of pancreatic cancer is associated with a strong desmoplastic reaction that consists of multiple cell types, molecular factors, and extracellular matrix [7]. This dense desmoplastic stromal reaction is one of the hallmarks of pancreatic cancer and plays a vital role in promoting angiogenesis while evading from immune cells [4, 8, 9]. Studies have uncovered a rich communication between stellate cells (fibroblasts) and cancer cells [4, 8, 9]. The abundance of PDGF (platelet derived growth factor), fibronectin, proteoglycans and hyaluronic acid distorts the normal pancreatic architecture and transforms it into a complex, abnormal configuration of seemingly impenetrable walls [7]. Accordingly, this extensive stroma is not only a passive barrier for the immune system but rather interacts with cancer cells and participates in its progression and invasion [7].

It is useful to examine the immune cells and receptors in pancreatic cancer based on their role in the development of an immune response and their correlation with prognosis. There are two immunological processes that determine the immune response against cancer cells: the effector process and the suppressor process. These cell types are summarized in Table 1 and Fig. 1.
Table 1

Cellular Microenvironment of Pancreatic Cancer

Cell

Role in pancreatic cancer

Relationship to outcome

Reference

NK

deactivated

↑tumor stage and ↓survival

[1113]

CD8+ T-Cell

deactivated

↑tumor stage and ↓survival

[5, 8, 13]

CD4+ Th1-Cell

↑tumor stage and ↓survival

[1214]

TAM (M1)

↑tumor stage

[4, 1214]

DC

deactivated

↑survival

[8, 13, 17, 18]

MDSC

↓survival

[5, 12, 16, 24]

Mast Cell

↑metastases

[9, 13]

T-regs

↓survival

[4, 5, 12, 22, 23]

TAM (M2)

↑stage and ↓survival

[4, 1214]

Fibroblast

↑stage and ↓survival

[12, 13, 25, 27]

CD4 + Th2 Cell

↑stage and ↓ survival

[5, 9, 1214, 16, 25]

↑ increase, ↓ decrease, DC dendritic cell, MDSC myeloid derived suppressor cell, NK natural killer cell, TAM tumor associated macrophage

Fig. 1

Pancreatic Cancer with Targeted Immunotherapy. DC (dendritic cell), GM-CSF (granulocyte macrophage colony stimulating factor), PD-1 (programmed cell death-1), PDL-1 (programmed cell death ligand-1), CTLA-4 (Cytotoxic T-lymphocyte associated protein-4), HSP (heat shock protein), TCR (T-cell receptor), MHC (major histocompatibility complex), vEGF-R (vascular epithelial growth factor-receptor), IDO (Indoleamine 2,3-dioxygenase), TGF (tumor growth factor), IL (interleukin), CD (cell differentiation), V (vaccine)

Effector immune cells

Natural killer cells (NK)

An increased number of NK cells have been shown to be associated with a better prognosis in a small set of 13 patients with pancreatic cancer [10], presumably due to their role in recognition and elimination of cancer cells. However, NK cells are typically found in a limited number in pancreatic cancer and often in a deactivated form due to the lack of NKG2D, a cell surface receptor found to be upregulated in activated NK cells [1113].

CD8 Cytotoxic and CD4 helper T-cells or tumor infiltrating lymphocytes (TILs)

The presence of TILs in pancreatic cancer has been well described and it may represent the most important element in PTME [8, 9, 14, 5]. Among these TILs, the memory (CD45RO) CD8 T-cells are thought to be the major anti-tumor effector cells and their density in resected pancreatic tumors was found to correlate with survival [8, 9]. On the other hand, the role of CD4 T-cells is more complex. The Th1, the effector form, activates antigen presenting cells (APC) such as dendritic cells (DCs) while the ineffective form (Th2) plays a major role in tumor tolerance [13, 5]. Although the presence of both CD8 and CD4 T-cells correlates with a better prognosis [4, 8, 15], they are found in small numbers in the PTME, possibly due to effect of stroma and suppressor immune cells [15]. In addition, the number of CD8 effector T-cells decreases during the malignant transformation of pre-cancer cells [5, 8]. Studies have shown that Th1 cells are found in disproportionately lower concentrations among pancreatic cancer cells than Th2, suggesting an ineffective immune response against tumor cells [5, 16].

Dendritic cells (DCs)

The presence of DCs in the PTIM is essential in order to generate an anti-tumor immune response and, similar to TILs, is associated with a better prognosis in pancreatic cancer [8, 17, 18]. However, DCs are present in low numbers in the PTME and often in an immature form [8, 17, 18], thus likely limiting their ability to present foreign antigens to T-cells.

Co-stimulatory receptors and ligands

CD40

Is a co-stimulatory molecule that is expressed on T-cells and binds to its ligand (CD40L) on APCs, leading to the activation of lymphocytes [13]. In a retrospective analysis of patients with pancreatic cancer, Unek et al., showed that the expression of CD40 in pancreatic cancer tissue samples correlates with a trend towards improved progression-free survival (PFS) and overall survival (OS) [19]. Accordingly, CD40 represents a promising target in pancreatic cancer as described below.

OX-40 (tumor necrosis factor receptor superfamily member 4)

Is a member of the TNF receptor family found on T- cells and acts as a secondary co-stimulatory molecule as it requires other co-stimulatory molecules to be expressed first prior to its activation. The expression of OX-40 is found in high concentrations on activated T-cells. In pancreatic cancer increased levels of OX-40 was reported to correlate with better survival but this data needs to be validated on a larger scale [10].

4-1BB (tumor necrosis factor receptor superfamily member 9)

Is also a member of the TNF receptor family and found on T-cells and NK cells. Upon interaction with its ligand 4-1BBL, it promotes T cell activation, particularly CD8 lymphocyte. 4-1BB also acts as a secondary co-stimulatory molecule, similar to OX-40 [20, 21]. However, there is currently no data available regarding the role of 4-1BB in the PTIM.

Suppressor immune cells

Tumor associated macrophages (TAMs)

These cells express the program cell death ligand (PD-L1) which is involved in immune suppression and T-cell apoptosis as described below. In PTIM, the presence of TAMs and it is association with poor outcomes and more frequent metastases has been well described [4, 13].

T-regulatory cells (CD4 + CD25 + FoxP3+) (T-regs)

T-regs are other subsets of TILs known for their immunosuppressive activity through the release of cytokines including TGF-β and IL-10. Based on few retrospective analyses, pancreatic tumors with low numbers of T-regs were found to have a significantly better survival compared to tumors with high numbers [4, 22, 23].

Myeloid derived suppressor Cell (MDSCs)

In pancreatic cancer, these cells were found in pre-malignant growths and increased in concentration as cancer cells grow suggesting a direct role in immune suppression and unrestricted cancer cell growth [5, 12, 16, 24]. Interestingly, high concentration of MDSCs in the peripheral blood was associated with poor outcomes in patients with pancreatic cancer [16]. Whether this correlation exists in the PTIM remains to be determined.

Fibroblasts/pancreatic stellate cell

Fibroblasts respond to a variety of molecules including CXCL12 (C-X-C motif chemokine 12) and produce VEGF (vascular endothelial growth factor) to stimulate angiogenesis in response to hypoxia or inflammation [7, 12, 13, 25]. In pancreatic cancer, the production of VEGF by fibroblasts is associated with cancer growth and worse prognosis [26, 27]. Therefore, the role of fibroblasts in the PTME is currently under intense investigation.

Mast cells

The role of mast cells in cancer has not been well-defined [9, 28, 29]. In pancreatic cancer, it has been suggested that low concentration of mast cells in the PTME correlates with increased survival [28] while increased concentration is associated with increased lymph node metastases based on retrospective analyses in small subsets of patients [29].

Co-Inhibitory Receptors and Ligands

Program-death (PD-1)

Is an inhibitory receptor that belongs to the B7-receptor family and interacts with its ligand PD-L1 (B7-H1) to down regulate signals by T-cells, leading to the induction of apoptosis in activated T-cells [13]. PD-1 is expressed on progenitor T cells, activated T- and B-lymphocytes, NK cells, and myeloid cells [13]. Patients with pancreatic cancer with PD-L1 positive tumors have a significantly worse prognosis than patients with PD-L1 negative tumors [27]. The PD-1/PD-L1 pathway is currently one of the most targeted pathways in cancer.

Cytotoxic T-lymphocyte associated protein-4 (CTLA-4)

Is a co-inhibitory molecule found on T- lymphocytes that deactivates these cells to induce apoptosis in response to interaction with APCs. This negative feedback loop is a key to normal immune function to prevent over-stimulation of T-cells and damage to healthy cells but is stimulated inappropriately in pancreatic cancer to create a microenvironment that promotes cancer growth rather than its recognition. CTLA-4 is overexpressed in pancreatic cancer cells and its overexpression was found to correlate negatively with survival in patients who underwent surgical resection [30].

CXCL12 (C-X-C motif chemokine ligand 12)

Is a chemokine that is found in high concentration in pancreatic cancer and is involved in fibroblast migration and proliferation. The increased concentration of CXCL12 in the cancer microenvironment creates a network of dense stroma restricting immune cells migration and recognition of cancer antigens. Feig et al., showed that the inhibition of this chemokine resulted in increased T-cell infiltration into pancreatic cancer in murine models [27].

T-cell immunoglobulin and mucin-domain containing molecule 3 (TIM-3)

Is a transmembrane protein that is involved in the regulation of Th1 lymphocytes. The interaction between TIM-3 and CD4 Th1 cells has been studied in pancreatic cancer patients and found to correlate with tumor vascular invasion [31]. However, the role of TIM-3 needs to be further characterized in pancreatic cancer and other malignancies.

Soluble lymphocyte activation gene-3 (LAG-3)

Is an important T-cell regulator that interacts with MHC class II molecules expressed on APCs. This interaction promotes activation and maturation of DCs but negatively regulates effector T-cells. LAG-3 has been shown to be necessary for T-regulatory cell activity and represents a novel target for therapy in pancreatic cancer [32].

Indoleamine 2,3-dioxygenase (IDO)

Is an enzyme involved in cleaving tryptophan into kynurenine. Tryptophan is required for T-cell activation and kynurenine leads to T-regs differentiation and chemotaxis [33]. Increased levels of IDO, as seen in pancreatic cancer, creates a microenvironment devoid of effector T-cells but rich in immunosuppressive T-regs [34]. IDO inhibitors are currently under investigation in pancreatic cancer and other malignancies (NCT02048709 and NCT02077881).

Galectins (Gal-1, Gal-3 and Gal-9)

Are immune modulating glycoproteins that are overexpressed in pancreatic cancer cells and thought to be involved in T-cell homeostasis. These glycoproteins have been shown to promote immune suppression in pancreatic cancer by promoting Th2 and T-reg transformation, restricting DC maturation and stimulating stellate cells [35, 36]. Their association with survival in pancreatic cancer has been conflicting, with several studies showing increased concentration associated with decreased survival [37, 38], while others showed an association with improved outcomes [39].

B7-H3

Is a member of the B7 ligand family that can be induced in activated dendritic cells, monocytes, and T cells leading to decrease Th1 type response and cytokine production. B7-H3 expression was found to correlate with lymph node metastases and advanced pathologic stage in patients with pancreatic cancer [40]. The inhibition of B7-H3 increased CD8+ TILs and inhibited tumor growth in mice [40].

Pancreatic cancer vaccines

Cancer vaccines aim to stimulate the immune system against tumor cells by generating humoral and/or cellular immune responses. Many forms of cancer vaccines exist but generally they can be divided into synthetic and cellular-based vaccines.

Synthetic vaccines (summarized in Table 2)

Table 2

Completed immunotherapy clinical trials

Treatment type

Target

N

Additional therapy

Cancer stage

Immunologic response

Clinical outcome

Ref

Peptide vaccines

CEA

23

None

Resected or Metastatic

↑ IFN-γ T cell response by ELISPOT with increasing vaccine dose

37 % survival at 32 months

[77]

CEA + MUC1

20

None

Metastatic

NR

mOS of 7.3 ms

[78]

Gastrin 17

154

None

Metastatic

74 % + ELISA

↑OS by 54 % vs placebo (p = 0.03)

[51]

Gastrin 17

383

None

Metastatic

Correlation between anti-gastrin17 titers and OS

No benefit

[53]

Gastrin 17

30

None

Metastatic

67 % + ELISA

↑OS (4 to 7.2 ms if + IR (p < 0.01)

[52]

GVAX + Mesothelin

90

Cyclophosphamide

Metastatic

NR

↑OS (4 to 6.2 ms)

[63]

Hedgehog

59

Gemcitabine

Metastatic

NR

mOS 10 ms

[79]

KRAS

23

None

Resected

85 % + DTH

10 year OS of 20 %

[56]

KRAS

48

GM-CSF

Resected(10) and Metastatic (38)

58 % + DTH

↑OS (2 to 5.4 ms if + IR (p = 0.0002)

[54]

KRAS

24

GM-CSF

Resected

11 % + DTH

mOS 20.3 ms

[55]

KRAS

39

Gemcitabine

Resected

47 % + ELISpot

↑OS by 21.7 wks if + IR (p < 0.01)

[57]

MUC1

16

SB-AS adjuvant

Resected

31 % + DHT

No benefit

[42]

MUC1

6

Incomplete Freund's

Metastatic

17 % + ELISA

No benefit

[41]

Telomerase

1062

Gemcitabine

Metastatic

NR

No benefit

[47]

Telomerase

520

Gemcitabine

Metastatic

NR

No benefit

[48]

Telomerase

48

GM-CSF

Metastatic

63 % + DHT

mOS of 4.3 ms if + IR (p < 0.01)

[50]

Telomerase

178

Gemcitabine

Metastatic

NR

No benefit

[49]

Trop-2

7

None

Metastatic

NR

No benefit

[80]

VEGF

607

Erlotinib + Gemcitabine

Metastatic

NR

No benefit

[44]

VEGF

535

Gemcitabine

Unresectable

NR

No benefit alone

[46]

VEGF

150

Gemcitabine

Unresectable

NR

No benefit

[46]

Wilm's Tumor gene-1

32

Gemcitabine

Unresectable

58 % + DTH

↑mOS by 7 ms if DHT + (p < 0.01)

[81]

Autologous: DC

MUC-1

49

Gemcitabine

Metastatic

↓65 % T-regs

2 CR, 5 PR ,10 SD

[59]

MUC1

17

None

Resected and Unresectable

NR

mOS of 9 ms

[82]

MUC-1

20

none

Metastatic

Correlation between CD38+ cells and OS

1 pt had remission of lung mets, 5 had stable disease. mOS 9.8 mos

[58]

MUC-1

10

None

Resected

No difference

30 % OS 4 years

[83]

MUC-1

2

None

Metastatic

↑117 % CD8+ MUC-1 specific cells

No benefit

[84]

Wilm's Tumor gene-1

10

Gemcitabine

Metastatic

57 % + DTH

↑OS if + DTH

[85]

Allogeneic

GM-CSF

60

5-FU

Resected

↑ mesothelin + ELISPOT

↑OS (53 % to 76 % if + IR)

[61]

GM-CSF

14

Adjuvant CRT

Resected

21 % + DTH

DFS of 25 ms if + R

[60]

GM-CSF

30

Cyclophosphamide

Metastatic

↑Mesothelin ELISPOT

No benefit

[62]

Adoptive cell transfer

Mesothelin

6

None

Metastatic

NR

33 % with stable disease

[65]

MUC1

28

None

Resected (20) and Unresectable (8)

↑10 % effector T-cells , ↓5.7 % Tregs

mOS 5 ms in unresectable,

19 % 3 year OS in resectable

[64]

MUC1

20

None

Unresected

↑CD8+ T-cells

mOS 9.8 ms,

1 year OS 20 %

[58]

Immune checkpoint inhibitor

CD40

21

Gemcitabine

Unresected (7) and Metastatic (20)

N/A

↑mOS by 1.7 ms vs gemcitabine alone, 1 patient had complete resolution of hepatic metasteses

[68]

CTLA-4

30

GVAX

Unresectable or metastatic

N/A

↑1 year OS by 20 % compared to GVAX alone

[75]

CTLA-4

27

none

Unresected (7) and Metastatic (20)

N/A

1 patient delayed regression of hepatic metasteses

[70]

PD-L1

14

none

Metastatic

N/A

No benefit

[69]

↑ increase, ↓ decrease, CR complete response, CRT chemoradiation, CTLA-4 Cytotoxic T-lymphocyte associated protein-4, DC dendritic cell, DTH delayed typed hypersensitivity, GM-CSF granulocyte macrophage colony stimulating factor, MDSC myeloid derived suppressor cell, mOS median overall survival, Ms months, N/A not applicable, NK natural killer cell, NR not reported, OS overall survival, PD-L1, programmed cell death ligand-1, PR partial response, R response, SD stable disease, TAM tumor associated macrophages, Wk weeks

Synthetic vaccines are typically made from whole protein or peptides that match a pre-determined antigen to induce a T- cell response. Despite multiple large trials targeting MUC1 [4143], VEGF [4446], telomerase [4750] and gastrin-17 [5153], none have shown a meaningful survival benefit. These trials, however, were able to show significant immune responses to the targeted antigens. Some trials using mutated RAS peptide vaccine alone [5456] or in combination with gemcitabine [57] have shown clinical benefit. Importantly, this benefit was mainly seen in patients who demonstrated positive immune responses [54, 56, 57].

Cellular-based vaccines (summarized in Table 2)

Cellular-based vaccines use cancer cells (either whole cells or cell lysates) as the source of the antigens, allowing the immune system to utilize multiple antigens rather than a single epitope. Overall the results of these trials are encouraging; however, each included a small number of patients making it difficult for meaningful interpretation. Cellular based vaccines can be divided into autologous or allogeneic vaccines based on the source of the cells.

Autologous vaccines

In this process, the patient’s own dendritic cells are isolated and pulsed with a specific antigen before being re-infused back to the patient. Multiple studies have used this vaccination approach targeting variety of antigens. MUC1 is one of the most targeted antigens given its overexpression in pancreatic cancer and its association with tumor invasion and metastasis. The clinical outcome of this vaccination method was not impressive; however, an interesting correlation with immune biomarkers was identified such as increased CD38 (a marker for activated lymphocytes) [58] and decreased T-regs [59].

Allogeneic vaccine

In this method of vaccination, a pancreatic cancer cell line is stimulated, usually with GM-CSF, in order to elicit an immune response when administered to patients with pancreatic cancer. A group at John Hopkins used this form of cancer vaccine (GVAX) in combination with 5-FU or chemoradiation in the adjuvant setting and showed an increase in PFS and OS in patients who developed an immune response against mesothelin [60, 61]. The same group also investigated GVAX in the metastatic setting in combination with low dose cyclophosphamide, to deplete T-regs, demonstrating an increase in mesothelin specific T-cell response with no survival benefit [62]. More recently, GVAX was combined with a Listeria vaccine that expresses mesothelin in 90 patients with metastatic disease. The combination of these 2 vaccines showed an improved OS compared to the allogeneic vaccine alone (6.1 vs 3.9 months, p = 0.01). Interestingly, patients who derived the most benefit of this combination were patients who received over 3 doses of the vaccine (9.7 vs 4.6 months, p = 0.01) and patients who received at least 2 previous chemotherapy regimens (5.1 vs 3.7 months, p = 0.001) [63]. This combination has currently a breakthrough designation by FDA while being investigated in patients with metastatic disease in a large ongoing clinical trial.

Adoptive T- cell transfer (summarized in Table 2)

In this approach the patient’s T-cells are expanded and activated ex vivo then re-infused back to the patient. Based on the source and the method used for T-cell activation, adoptive T- cell transfer could be classified into: Tumor infiltrating lymphocytes (TILs), engineered T- cells that express a specific cancer T-cell receptor (TCR), and T- cells that express a chimeric antigen receptor (CAR). This methodology of immunotherapy had gained a lot of attention recently due to promising clinical outcomes in hematological malignancies. However, the efficacy of adoptive T- cell transfer remains to be determined in solid tumors including pancreatic cancer. Kawaoka et al., investigated MUC1-specific cytotoxic T lymphocytes (CTLs) in 28 patients and showed 19 % 3-year survival in patients with resectable disease along with increased effector lymphocytes and decreased T-regs [64]. More recently, the University of Pennsylvania group presented their experience using autologous T- cells modified with a chimeric antigen receptor (CAR) that recognizes mesothelin in pancreatic cancer patients with refractory metastatic disease. Of the 6 patients treated 2 had stable disease with one patient had a decreased PET avidity of hepatic metastases. Overall, the treatment was well tolerated [65]. The carcinoembryonic antigen (CEA) is another attractive target in pancreatic cancer that is currently been explored in clinical trials (NCT01723306, NCT00004178 and NCT01212887). New generations of CAR therapies are under investigation with a focus on increasing their activities and specificities and decreasing their toxicities. The CAR T-cells efficacy could be enhanced by engineering the intracellular domain to contain co-stimulatory molecules such as 41BB and OX40 or combining CAR T-cells therapy with immune modulators such as cyclophosphamide in order to deplete T-regulatory cells (NCT02465983) or immune checkpoint inhibitors such as CTLA-4 and anti-PD1 antibodies.

Immune checkpoint inhibitors and co-stimulatory agonists (summarized in Table 2)

Immune checkpoint inhibitors represent a paradigm shift in cancer treatment due to their promising clinical activities in melanoma and other malignancies [66, 67]. However, a limited number of studies targeting these immune checkpoints have been completed in pancreatic cancer. The first study to investigate the co-stimulatory agonists in pancreatic cancer used CD40 agonist in combination with gemcitabine in 21 patients with locally advanced or metastatic disease. This study demonstrated promising outcomes with an improvement of median OS compared to gemcitabine alone and one patient having a complete resolution of his liver metastases [68]. In the area of immune checkpoint inhibitors, both CTLA-4 and PD-L1 inhibitors were investigated in patients with locally advanced or metastatic pancreatic cancer in 2 clinical trials. The clinical outcomes were disappointing, although, only small number of patients were treated on both trials [69, 70]. To date, the only immune checkpoint inhibitor to show activity in pancreatic cancer is MEDI4736 (anti-PD-L1), which showed a PR rate of 8 % in a preliminary analysis of this going trial [71]. While this suggests a response can be achieved with single immunotherapy, it remains dismal and maybe improved by combination therapy. This approach is currently being investigated in few ongoing trials as detailed in Table 3.
Table 3

On-going immunotherapy clinical trials

Treatment type

Phase

Target

N

Additional therapy

Stage

Identifier

Chimeric antibody

I,II

Ensituximab

116

None

Metastatic

NCT01040000a

DNA vaccine

I

VEGFR-2

72

None

Metastatic

NCT01486329a

Fungal vector vaccine

II

RAS

176

Gemcitabine

Resected

NCT00300950a

Viral vector vaccine

I

Small Pox Virus

36

None

Metastatic

NCT00574977a

Allogeneic vaccine

I

CEA

48

GM-CSF

Metastatic

NCT00028496a

I

Donor Lymphocyte

37

None

Metastatic

NCT00161187a

I

Dendritic cells

12

Poly-ICLC

Unresectable

NCT01677962

II

GM-CSF

60

Cetuximab + Cyclophosphamide

Metastatic

NCT00305760a

II

GVAX

56

None

Metastatic

NCT00389610

II

GVAX

87

Cyclophosphamide

Resectable

NCT0072744

II

GVAX

19

Cyclophosphamide, Radiation, FOLFIRINOX

Resected

NCT01595321

II

GVAX +/- Mesothelin

93

Cyclophosphamide

Metastatic

NCT01417000

II

GVAX +/- Mesothelin

240

Gemcitabine, Capecitabine, 5-FU, Irinotecan, Erlotinib or Cyclophosphamide

Metastatic

NCT02004262

II

IFN-α + GM-CSF

14

Cyclophosphamide

Metastatic

NCT00002773a

III

Virulizin

400

Gemcitabine +/- 5-FU

Metastatic

NCT00040092a

Autologous vaccine

I

CEA

24

None

Metastatic

NCT00004604a

I

CEA

14

None

Metastatic

NCT00027534a

I

CEA

24

Denileukin Diftitox

Metastatic

NCT00128622a

II

CEA

48

IL-2

Metastatic

NCT01723306

I

Dendritic Cells

2

Gemcitabine + Stereotactic Radiosurgery

Metastatic

NCT00547144a

II

KLH

35

Radiation

Metastatic

NCT00868114

Immunotherapy

I

B7-H3

93

none

All

NCT01391143

I

CD40

10

Gemcitabine + nab-paclitaxel

Metastatic

NCT02588443

I

CD40

10

Gemcitabine

resected

NCT01456585a

II

CTLA-4

82

None

Metastatic

NCT00112580a

I

CTLA-4

37

Gemcitabine

Metastatic

NCT00556023a

I

CTLA-4

28

Gemcitabine

Metastatic

NCT01473940

II

CTLA-4 + GVAX

92

FOLFIRINOX

Metastatic

NCT01896869

II

IDO

98

Gemcitabine + nab-paclitaxel

metastatic

NCT02077881

I

IL-1-Ra

13

FOLFIRINOX

Metastatic

NCT02021422

I/II

PD-1

56

Capecitabine + Radiation

Resectable and Borderline Resectable

NCT02305186

I

PD-L1

1038

none

All

NCT01693562

Peptide vaccine

I,II

Alpha (1, 3) galactosyltransferase

7

None

Metastatic

NCT00255827a

III

Alpha (1, 3) galactosyltransferase

280

FOLFIRINOX

Locally Advanced

NCT01836432

III

Alpha (1,3) galactosyltransferase

722

Gemcitabine, 5-FU, radiation

Resected

NCT01072981

I,II

CEA

28

None

Metastatic

NCT00529984a

I

CEA + MUC1

18

None

Unresectable

NCT00669734

I

hCG-β

36

None

Metastatic

NCT00648102a

I

hCG-β

48

None

Metastatic

NCT00709462a

I

Heat Shock Protein

16

None

Resected

NCT00003025a

I/II

Hedgehog

122

Gemcitabine

Metastatic

NCT01130142a

I

Hedgehog

21

FOLFIRINOX

Unresectable

NCT01383538

I

MUC1

25

None

Resected or Locally Advanced

NCT00008099a

I/II

MUC5AC

90

Gemcitabine + nab-paclitaxel

Unresectable

NCT01834235

I

P53

12

None

Unresectable

NCT01191684a

II

P53 + RAS

70

IL-2

Metastatic

NCT00019084a

I

RAS

7

None

Metastatic

NCT00006387a

I

RAS

33

None

Metastatic

NCT00019006a

III

Telomerase

1110

Capecitabine + Gemcitabine

Metastatic

NCT00425360a

I

TGF-β

168

Gemcitabine

Resectable and unresectable

NCT01373164

I

Trophoblast glycoprotein

44

None

Metastatic

NCT00056537a

I/II

VEGF

17

Gemcitabine

Unresectable

NCT00655785a

I

VEGFR-2

21

Gemcitabine

Metastatic

NCT00622622a

5-FU 5-flurouracil, CEA Carcinoembryonic antigen, CTLA-4 Cytotoxic T-lymphocyte associated protein-4, FOLFIRINOX folinic acid, fluorouracil, irinotecan, oxaliplatin, GM-CSF granulocyte macrophage colony stimulating factor, hCG Human chorionic gonadotropin, IDO indoleamine 2,3-dioxygenase, IFN interferon, IL-2 interleukin-2, KLH keyhole limpet hemocyanin, MUC mucin, N number, PD programmed death, PD-L programmed death ligand, Poly-ICLC carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly-L-lysine double-stranded RNA, TGF Transforming growth factor, VEGF Vascular endothelial growth factor, VEGF-R Vascular endothelial growth factor receptor

aStudy listed as complete but results not published

Combination therapy

Due to the lack of meaningful clinical benefits of cancer vaccines, the potential positive immunological effect of chemotherapy and radiation therapy, and the promising outcomes of immune checkpoint inhibitors, the focus has shifted towards combining these modalities. Gemcitabine, a standard chemotherapy that is used traditionally to treat pancreatic cancer, has been found to mediate immunological effects such as tumor associated antigen cross presentation by dendritic cells and the induction and expansion of cytotoxic T cells responses in addition to reduce the number of myeloid suppressor cells [72, 73]. Radiation therapy can also increase the immunogenic properties of tumor cells by enhancing MHC class I expression, thereby increasing their vulnerability to CTLs. Another frequent effect of DNA damage inflicted by radiotherapy or chemotherapy is the increase in the expression of death receptors (in particular Fas/CD95 and TNF-related apoptosis-inducing ligand [TRAIL] receptors, enabling lysis of the tumor cells by Fas/CD95 ligand and TRAIL-positive immune effectors [74]. As detailed in Table 3, the majority of ongoing trials investigate a combination strategy of the immunotherapy with chemotherapy, radiation or both. Of interest are multiple trials targeting mesothelin and/or GVAX with chemoradiation and multiple immune checkpoint inhibitors combined with chemotherapy. Our group is currently investigating the immunological effect of the combination of chemoradiation and anti-PD-1 as a neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer compared to neoadjuvant chemoradiation alone (NCT02305186). This neoadjuvant setting will allow investigators to study the effect of combination therapy on the tumor microenvironment. Another promising combination by the Hopkins group combined GVAX with anti-CTLA-4 and demonstrated a 1-year improvement in OS by 20 % compared to GVAX and cyclophosphamide alone [75].

Conclusion

Despite the ongoing efforts outlined in this review, the prognosis of pancreatic cancer remains dismal. With the recent progress in cancer immunotherapy, there are glimmers of hope in new immune targets with more being identified each year. These advancements are moving from the bench to the bedside at a rapid pace, with the hope of translating into improvements in clinical outcomes. We believe that immunotherapy represents a promising modality in pancreatic cancer. However, there still remains much to be learned about the pancreatic immune microenvironment and its role in the immune escape of cancer cells. In order to develop an active strategy to enhance the immune response against pancreatic cancer that could be translated to a promising clinical outcome we must focus our efforts on increasing the density of the intratumoral effector T-cells; decreasing or inhibiting the immunosuppressive cells and receptors; and understanding the role of the stromal reaction and its interaction with pancreatic cancer immune microenvironment. Indeed, the recent encouraging data of patients with mismatch-repair deficient colorectal cancer responding to pembrolizumab requires further investigation, particularly as it may be relevant for a small number of patients with pancreatic cancer [76]. Improved response rates and survival benefits may be achieved by using combination therapies; identifying novel biomarkers in order to select the group of patients who may drive the most benefit of cancer immunotherapy; and implementing novel clinical trials designs that allow for tumor samples collection in order to understand the mechanism of action and resistance of pancreatic cancer to immunotherapy.

Abbreviations

↑: 

increase

↓: 

decrease

4-1BB: 

Tumor Necrosis Factor Receptor Superfamily Member 9

APC: 

antigen presenting cell

CD: 

cell differentiation

CR: 

complete response

CRT: 

chemoradiation

CTLA-4: 

Cytotoxic T-lymphocyte associated protein-4

CXCL12: 

C-X-C motif chemokine 12

DC: 

dendritic cell

DTH: 

delayed typed hypersensitivity

ELISA: 

enzyme linked immunosorbent assay

FOLFIRINOX: 

folinic acid, fluorouracil, irinotecan, oxaliplatin

Gal: 

Galectins

GM-CSF: 

granulocyte macrophage colony stimulating factor

HSP: 

heat shock protein

IDO: 

Indoleamine 2,3-dioxygenase

IFN-γ: 

interferon-gamma

IL: 

interleukin

LAG-3: 

Soluble Lymphocyte Activation Gene-3

MDSC: 

myeloid derived suppressor cell

MHC: 

major histocompatibility complex

mOS: 

median overall survival

ms: 

months

NA: 

not applicable

NK: 

natural killer cell

NR: 

not reported

OS: 

overall survival

OX-40: 

Tumor Necrosis Factor Receptor Superfamily Member 4

PD-1: 

programmed cell death-1

PDGF: 

platelet derived growth factor

PD-L1: 

programmed cell death-ligand 1

PR: 

partial response

PTME: 

pancreatic tumor microenvironment

R: 

response

SD: 

stable disease

TAM: 

tumor associated macrophages

TCR: 

T-cell receptor

TGF: 

tumor growth factor

TIL: 

tumor infiltrating lymphocyte

TIM-3: 

T-cell Immunoglobulin and mucin-domain containing molecule 3

vEGF: 

vascular epithelial growth factor

vEGF-R: 

vascular epithelial growth factor-receptor

Declarations

Acknowledgements

No additional acknowledgements other than those listed as authors. There were no sources of funding for this review.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Medicine, Division of Hematology-Oncology, University of Virginia Health System
(2)
Department of Surgery, Division of Hepatobiliary Surgery, University of Virginia Health System
(3)
Department of Surgery, Division of Surgical Oncology, University of Virginia Health System

References

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.PubMedView ArticleGoogle Scholar
  2. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1252–61.PubMed CentralPubMedView ArticleGoogle Scholar
  3. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21.PubMedView ArticleGoogle Scholar
  4. Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer. 2013;108(4):914–23.PubMed CentralPubMedView ArticleGoogle Scholar
  5. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.PubMedView ArticleGoogle Scholar
  6. Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S, Galban CJ, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012;122(2):639–53.PubMed CentralPubMedView ArticleGoogle Scholar
  7. Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res. 2012;18(16):4266–76.PubMed CentralPubMedView ArticleGoogle Scholar
  8. Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, et al. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas. 2004;28(1):e26–31.PubMedView ArticleGoogle Scholar
  9. Protti MP, De Monte L. Immune infiltrates as predictive markers of survival in pancreatic cancer patients. Front Physiol. 2013;4:210.PubMed CentralPubMedView ArticleGoogle Scholar
  10. Davis M, Conlon K, Bohac GC, Barcenas J, Leslie W, Watkins L, et al. Effect of pemetrexed on innate immune killer cells and adaptive immune T cells in subjects with adenocarcinoma of the pancreas. J Immunother. 2012;35(8):629–40.PubMedView ArticleGoogle Scholar
  11. Duan X, Deng L, Chen X, Lu Y, Zhang Q, Zhang K, et al. Clinical significance of the immunostimulatory MHC class I chain-related molecule A and NKG2D receptor on NK cells in pancreatic cancer. Med Oncol. 2011;28(2):466–74.PubMedView ArticleGoogle Scholar
  12. Sideras K, Braat H, Kwekkeboom J, van Eijck CH, Peppelenbosch MP, Sleijfer S, et al. Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies. Cancer Treat Rev. 2014;40(4):513–22.PubMedView ArticleGoogle Scholar
  13. Wachsmann MB, Pop LM, Vitetta ES. Pancreatic ductal adenocarcinoma: a review of immunologic aspects. J Investig Med. 2012;60(4):643–63.PubMed CentralPubMedGoogle Scholar
  14. Disis ML. Immune regulation of cancer. J Clin Oncol. 2010;28(29):4531–8.PubMed CentralPubMedView ArticleGoogle Scholar
  15. Vonderheide RH, Bayne LJ. Inflammatory networks and immune surveillance of pancreatic carcinoma. Curr Opin Immunol. 2013;25(2):200–5.PubMed CentralPubMedView ArticleGoogle Scholar
  16. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother. 2011;60(10):1419–30.PubMed CentralPubMedView ArticleGoogle Scholar
  17. Yamamoto T, Yanagimoto H, Satoi S, Toyokawa H, Yamao J, Kim S, et al. Circulating myeloid dendritic cells as prognostic factors in patients with pancreatic cancer who have undergone surgical resection. J Surg Res. 2012;173(2):299–308.PubMedView ArticleGoogle Scholar
  18. Tjomsland V, Spangeus A, Sandstrom P, Borch K, Messmer D, Larsson M. Semi mature blood dendritic cells exist in patients with ductal pancreatic adenocarcinoma owing to inflammatory factors released from the tumor. PLoS One. 2010;5(10):e13441.PubMed CentralPubMedView ArticleGoogle Scholar
  19. Unek T, Unek IT, Agalar AA, Sagol O, Ellidokuz H, Ertener O, et al. CD40 expression in pancreatic cancer. Hepatogastroenterology. 2013;60(128):2085–93.PubMedGoogle Scholar
  20. Moran AE, Kovacsovics-Bankowski M, Weinberg AD. The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol. 2013;25(2):230–7.PubMedView ArticleGoogle Scholar
  21. Cheuk AT, Mufti GJ, Guinn BA. Role of 4-1BB:4-1BB ligand in cancer immunotherapy. Cancer Gene Ther. 2004;11(3):215–26.PubMedView ArticleGoogle Scholar
  22. Ikemoto T, Yamaguchi T, Morine Y, Imura S, Soejima Y, Fujii M, et al. Clinical roles of increased populations of Foxp3 + CD4+ T cells in peripheral blood from advanced pancreatic cancer patients. Pancreas. 2006;33(4):386–90.PubMedView ArticleGoogle Scholar
  23. Yamamoto T, Yanagimoto H, Satoi S, Toyokawa H, Hirooka S, Yamaki S, et al. Circulating CD4 + CD25+ regulatory T cells in patients with pancreatic cancer. Pancreas. 2012;41(3):409–15.PubMedView ArticleGoogle Scholar
  24. Zhao F, Obermann S, von Wasielewski R, Haile L, Manns MP, Korangy F, et al. Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma. Immunology. 2009;128(1):141–9.PubMed CentralPubMedView ArticleGoogle Scholar
  25. De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, 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. 2011;208(3):469–78.PubMed CentralPubMedView ArticleGoogle Scholar
  26. Abdollahi A, Schwager C, Kleeff J, Esposito I, Domhan S, Peschke P, et al. Transcriptional network governing the angiogenic switch in human pancreatic cancer. Proc Natl Acad Sci U S A. 2007;104(31):12890–5.PubMed CentralPubMedView ArticleGoogle Scholar
  27. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212–7.PubMed CentralPubMedView ArticleGoogle Scholar
  28. Strouch MJ, Cheon EC, Salabat MR, et al. Crosstalk between mast cells and pancreatic cancer cells contributes to pancreatic tumor progression. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16(8):2257–65.View ArticleGoogle Scholar
  29. Esposito I, Menicagli M, Funel N, et al. Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol. 2004;57(6):630–6.PubMed CentralPubMedView ArticleGoogle Scholar
  30. Loos M, Hedderich DM, Ottenhausen M, Giese NA, Laschinger M, Esposito I, et al. Expression of the costimulatory molecule B7-H3 is associated with prolonged survival in human pancreatic cancer. BMC Cancer. 2009;9:463-2407-9-463.View ArticleGoogle Scholar
  31. Tong D, Zhou Y, Chen W, Deng Y, Li L, Jia Z, et al. T cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms and susceptibility to pancreatic cancer. Mol Biol Rep. 2012;39(11):9941–6.PubMedView ArticleGoogle Scholar
  32. Wang-Gillam A, Plambeck-Suess S, Goedegebuure P, Simon PO, Mitchem JB, Hornick JR, et al. A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma. Invest New Drugs. 2013;31(3):707–13.PubMed CentralPubMedView ArticleGoogle Scholar
  33. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol. 2006;176(11):6752–61.PubMedView ArticleGoogle Scholar
  34. Witkiewicz A, Williams TK, Cozzitorto J, Durkan B, Showalter SL, Yeo CJ, et al. Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. J Am Coll Surg. 2008;206(5):849–54. discussion 854-6.PubMedView ArticleGoogle Scholar
  35. Cooper D, Ilarregui JM, Pesoa SA, Croci DO, Perretti M, Rabinovich GA. Multiple functional targets of the immunoregulatory activity of galectin-1: Control of immune cell trafficking, dendritic cell physiology, and T-cell fate. Methods Enzymol. 2010;480:199–244.PubMedView ArticleGoogle Scholar
  36. Fitzner B, Walzel H, Sparmann G, Emmrich J, Liebe S, Jaster R. Galectin-1 is an inductor of pancreatic stellate cell activation. Cell Signal. 2005;17(10):1240–7.PubMedView ArticleGoogle Scholar
  37. Chung JC, Oh MJ, Choi SH, Bae CD. Proteomic analysis to identify biomarker proteins in pancreatic ductal adenocarcinoma. ANZ J Surg. 2008;78(4):245–51.PubMedView ArticleGoogle Scholar
  38. Kuramitsu Y, Taba K, Ryozawa S, Yoshida K, Zhang X, Tanaka T, et al. Identification of up- and down-regulated proteins in gemcitabine-resistant pancreatic cancer cells using two-dimensional gel electrophoresis and mass spectrometry. Anticancer Res. 2010;30(9):3367–72.PubMedGoogle Scholar
  39. Chen R, Pan S, Ottenhof NA, de Wilde RF, Wolfgang CL, Lane Z, et al. Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma. Cancer Biol Ther. 2012;13(10):899–907.PubMed CentralPubMedView ArticleGoogle Scholar
  40. Yamato I, Sho M, Nomi T, Akahori T, Shimada K, Hotta K, et al. Clinical importance of B7-H3 expression in human pancreatic cancer. Br J Cancer. 2009;101(10):1709–16.PubMed CentralPubMedView ArticleGoogle Scholar
  41. Yamamoto K, Ueno T, Kawaoka T, Hazama S, Fukui M, Suehiro Y, et al. MUC1 peptide vaccination in patients with advanced pancreas or biliary tract cancer. Anticancer Res. 2005;25(5):3575–9.PubMedGoogle Scholar
  42. Ramanathan RK, Lee KM, McKolanis J, Hitbold E, Schraut W, Moser AJ, et al. Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer. Cancer Immunol Immunother. 2005;54(3):254–64.PubMedView ArticleGoogle Scholar
  43. Petrulio CA, Kaufman HL. Development of the PANVAC-VF vaccine for pancreatic cancer. Expert Rev Vaccines. 2006;5(1):9–19.PubMedView ArticleGoogle Scholar
  44. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27(13):2231–7.PubMedView ArticleGoogle Scholar
  45. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010;28(22):3617–22.PubMed CentralPubMedView ArticleGoogle Scholar
  46. Yamaue H, Tani T, Miyazawa M, Yamao K, Mizuno N, Okusaka T, et al. Phase II/III clinical trial with VEGFR2-epitope peptide and gemcitabine for patients with locally advanced, metastatic, or unresectable pancreatic cancer: Pegasus-PC study. J Clin Oncol. 2013;4:abstr 223.Google Scholar
  47. Middleton G, Silcocks P, Cox T, Valle J, Wadsley J, Propper D, 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 3 trial. Lancet Oncol. 2014;15(8):829–40.PubMedView ArticleGoogle Scholar
  48. Schmidt J. Pharmexa Stops One of Two Phase III Trials. 2008; Available at: http://www.drugs.com/news/pharmexa-stops-one-two-phase-iii-trials-8180.html, 2014.Accessed 16 Feb 2016.
  49. 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 (Meeting Abstracts) May 2009;27(no. 15S 4601).Google Scholar
  50. Bernhardt SL, Gjertsen MK, Trachsel S, Moller M, Eriksen JA, Meo M, et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: A dose escalating phase I/II study. Br J Cancer. 2006;95(11):1474–82.PubMed CentralPubMedView ArticleGoogle Scholar
  51. Gilliam AD, Broome P, Topuzov EG, Garin AM, Pulay I, Humphreys J, et al. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. Pancreas. 2012;41(3):374–9.PubMedView ArticleGoogle Scholar
  52. Brett BT, Smith SC, Bouvier CV, Michaeli D, Hochhauser D, Davidson BR, et al. Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer. J Clin Oncol. 2002;20(20):4225–31.PubMedView ArticleGoogle Scholar
  53. Shapiro J, Marshall J, Karasek P, et al. G17DT + gemcitabine versus placebo + gemcitabine in untreated subjects with locally advanced, recurrent or metastatic adenocarcinoma of the pancreas: results of a randomized, double-blinded, multinational, multicenter study. J Clin Oncol. 2005;23(suppl):4012.Google Scholar
  54. Gjertsen MK, Buanes T, Rosseland AR, Bakka A, Gladhaug I, Soreide O, 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. 2001;92(3):441–50.PubMedView ArticleGoogle Scholar
  55. Abou-Alfa GK, Chapman PB, Feilchenfeldt J, Brennan MF, Capanu M, Gansukh B, et al. Targeting mutated K-ras in pancreatic adenocarcinoma using an adjuvant vaccine. Am J Clin Oncol. 2011;34(3):321–5.PubMedView ArticleGoogle Scholar
  56. Weden S, Klemp M, Gladhaug IP, Moller M, Eriksen JA, Gaudernack G, et al. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int J Cancer. 2011;128(5):1120–8.PubMedView ArticleGoogle Scholar
  57. Muscarella P et al. A randomized, placebo controlled, doubled, blind, multicenter phase 2 adjuvant trial of the efficacy, immunogenicity, and safety of GI-4000 plus Gem vs Gem alone in patients with resected pancreas cancer with activating Ras mutations/survival and immunology analysis of the R1 Subgroup. J Clin Oncol. 2012;30(suppl):astr #e14501.Google Scholar
  58. Kondo H, Hazama S, Kawaoka T, Yoshino S, Yoshida S, Tokuno K, et al. Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes. Anticancer Res. 2008;28(1B):379–87.PubMedGoogle Scholar
  59. Kimura Y, Tsukada J, Tomoda T, Takahashi H, Imai K, Shimamura K, 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. 2012;41(2):195–205.PubMedView ArticleGoogle Scholar
  60. Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol. 2001;19(1):145–56.PubMedGoogle Scholar
  61. Lutz E, Yeo CJ, Lillemoe KD, Biedrzycki B, Kobrin B, Herman J, 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. 2011;253(2):328–35.PubMed CentralPubMedView ArticleGoogle Scholar
  62. Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, 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. 2008;14(5):1455–63.PubMed CentralPubMedView ArticleGoogle Scholar
  63. Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, 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. 2015;33(12):1325–33.PubMedView ArticleGoogle Scholar
  64. Kawaoka T, Oka M, Takashima M, Ueno T, Yamamoto K, Yahara N, et al. Adoptive immunotherapy for pancreatic cancer: cytotoxic T lymphocytes stimulated by the MUC1-expressing human pancreatic cancer cell line YPK-1. Oncol Rep. 2008;20(1):155–63.PubMedGoogle Scholar
  65. Beatty GL. Safety and antitumor activity of chimeric antigen receptor modified T cells in patients with chemotherapy refractory metastatic pancreatic cancer. 2015 ASCO Annual Meeting; 2015.Google Scholar
  66. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.PubMed CentralPubMedView ArticleGoogle Scholar
  67. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.PubMedView ArticleGoogle Scholar
  68. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331(6024):1612–6.PubMed CentralPubMedView ArticleGoogle Scholar
  69. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.PubMed CentralPubMedView ArticleGoogle Scholar
  70. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33(8):828–33.PubMedView ArticleGoogle Scholar
  71. Segal NH, Anto SJ, Brahmer JR, et al. Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody. J Clin Oncol. 2014;32(5 s):abstr 3002.Google Scholar
  72. Plate JM, Plate AE, Shott S, Bograd S, Harris JE. Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol Immunother. 2005;54(9):915–25.PubMedView ArticleGoogle Scholar
  73. Correale P, Cusi MG, Del Vecchio MT, Aquino A, Prete SP, Tsang KY, et al. Dendritic cell-mediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro. J Immunol. 2005;175(2):820–8.PubMedView ArticleGoogle Scholar
  74. Kershaw MH, Devaud C, John LB, Westwood JA, Darcy PK. Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment. Oncoimmunology. 2013;2(9):e25962.PubMed CentralPubMedView ArticleGoogle Scholar
  75. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, 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. 2013;36(7):382–9.PubMed CentralPubMedView ArticleGoogle Scholar
  76. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372(26):2509–20.PubMedView ArticleGoogle Scholar
  77. Geynisman DM, Zha Y, Kunnavakkam R, Aklilu M, Catenacci DV, Polite BN, et al. A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma. J Immunother Cancer. 2013;1:8-1426-1-8. eCollection 2013.Google Scholar
  78. Schuetz T, Kaufman H, Marshall J, Safran H. Extended survival in second-line pancreatic cancer after therapeutic vaccination.2005. 16 suppl 2576. ASCO Annual Meeting.Google Scholar
  79. 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, 2014 (suppl 3; abstr 257). ASCO Annual Meeting.Google Scholar
  80. 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, 2014 (suppl; abstr 3032). ASCO Annual MeetingGoogle Scholar
  81. Nishida S, Koido S, Takeda Y, Homma S, Komita H, Takahara A, et al. Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. J Immunother. 2014;37(2):105–14.PubMed CentralPubMedView ArticleGoogle Scholar
  82. 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. 2009;29(3):831–6.PubMedGoogle Scholar
  83. Lepisto AJ, Moser AJ, Zeh H, Lee K, Bartlett D, McKolanis JR, 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. 2008;6(B):955–64.PubMed CentralPubMedGoogle Scholar
  84. 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. 2002;51(11-12):669–73.PubMedView ArticleGoogle Scholar
  85. Koido S, Homma S, Okamoto M, Mori M, and Yoshizaki S. Dendritic cells pulsed with Wilms′ tumor gene 1 (WT1)-specific and MHC class I and II-restricted epitopes with gemcitabine induce antitumor immune responses in patients with advanced pancreatic cancer. Cancer Research. October 1, 2014;74:CT223. AACR Annual Meeting.Google Scholar

Copyright

© Kunk et al. 2016

Advertisement