B cells are not only producers of antibodies, but also contribute to immune regulation or act as potent antigen-presenting cells. The potential of B cells for cellular therapy is still largely underestimated, despite their multiple diverse effector functions. The CD40L/CD40 signaling pathway is the most potent activator of antigen presentation capacity in B lymphocytes. CD40-activated B cells are potent antigen-presenting cells that induce specific T-cell responses in vitro and in vivo. In preclinical cancer models in mice and dogs, CD40-activated B cell-based cancer immunotherapy was able to induce effective antitumor immunity. So far, there have been only few early-stage clinical studies involving B cell-based cancer vaccines. These trials indicate that B cell-based immunotherapy is generally safe and associated with little toxicity. Furthermore, these studies suggest that B-cell immunotherapy can elicit antitumor T-cell responses. Alongside the recent advances in cellular therapies in general, major obstacles for generation of good manufacturing practice-manufactured B-cell immunotherapies have been overcome. Thus, a first clinical trial involving CD40-activated B cells might be in reach.

B cells are best known for their role as producers of antibodies. Over recent decades, it has become clear that B cells serve much more diverse functions than just antibody production. B cells are an important source of cytokines and chemokines and thus contribute to the regulation of immune responses. Depending on the mode of activation, the subtype involved, or the microenvironment, B cells either contribute to upregulation of T-cell responses or they can exert immunoregulatory functions and participate in the downregulation of T-cell immunity [reviewed in 1].

In the 1980s, the ability of B cells to act as antigen-presenting cells (APCs) became increasingly appreciated. However, concurrently dendritic cells (DCs) were characterized as potent professional APCs. Due to their potent antigen-presenting capacity, DCs were regarded as the primary APCs for the induction of T-cell immunity and became the main focus for further development of cellular cancer vaccines. However, DCs possess several important drawbacks as APCs for cellular cancer vaccines. It is difficult and relatively expensive to generate sufficient amounts of DCs for repeated vaccinations. Furthermore, there are a large variety of protocols using different cytokine cocktails to generate DCs for immunotherapeutic purposes. Little is known about which protocol is optimal. Therefore, several research groups have investigated alternative cellular adjuvants.

Activated B cells become potent professional APCs only when appropriately activated. Soon after CD40 and its ligand CD40L (also named CD154) were first described, it became clear that CD40L/CD40 signaling was among the most potent stimuli for the activation of B cells [2, 3]. Classically, CD40L is expressed on activated CD4+ T cells and, thus, is essential for a thymus-dependent B-cell response and for the development of a humoral and cellular immune response. CD40L is a type II transmembrane protein, which exists as a trimer, inducing oligomerization of CD40 upon binding [4], a process that is critical for signaling via the CD40 receptor and likely accounts for the diverse biologic activities induced by different monoclonal antibodies [5]. CD40 acts a transmembrane signal transducer activating intracellular kinases and transcription factors within the cell. More specifically, recruitment of TRAF proteins to the cytoplasmic tail of CD40 activates the canonical and noncanonical NFκB pathways, MAP kinases, phosphoinositide 3-kinases, and the phospholipase Cγ pathway [reviewed in 6]. Independent of TRAF proteins, Janus family kinase 3 can directly bind to the cytoplasmic tail of CD40 inducing phosphorylation of STAT5 [7, 8]. These signaling cascades in B cells eventually promote germinal center formation, immunoglobulin isotype switch, somatic hypermutation, and formation of long-loved plasma cells or memory B cells [9-12]. Moreover, the CD40L/CD40 interaction is involved in the cellular immune response by regulating the costimulatory activity of APCs [13] and thus influences T-cell priming and effector functions. This discovery resulted in the development of cell culture systems that allow the activation and expansion of B cells from peripheral blood [14]. In the late 1990s, Schultze et al. [15] proposed in vitro-generated CD40-activated B cells (CD40B cells) as an alternative to DCs as cellular adjuvant for cancer immunotherapy. Ex vivo-generated CD40B cells possess potent immunostimulatory properties and are capable of priming CD4 and CD8 T cells in vitro and in vivo [16-18]. Over the subsequent years, the antigen-presenting function of B cells was characterized in more detail and the concept of B cell-based cancer vaccines was increasingly refined. Several experimental studies in different tumor models confirmed that vaccination with CD40B cells could induce effective antitumor CD4 and CD8 T-cell responses.

In 2005, Biagi et al. [19] reported the first small clinical trial of a cancer vaccine that used CD40B cells as cellular adjuvant. They transduced autologous leukemic B cells isolated from patients with chronic lymphocytic leukemia (CLL) with an adenoviral vector that contained the human CD40L gene and reinfused these cells together with transduced autologous CLL cells that expressed interleukin (IL)-2. Three of 9 patients demonstrated a greater than 50% reduction in lymph node size. Unfortunately, the induced T-cell responses were only transient and unable to overcome tumor-induced immunosuppression in the long term. In spite of these disappointing results, this study provided a first proof-of-concept for B cell-based cancer immunotherapy and demonstrated that antitumor T-cell responses can be induced by activated antigen-presenting B lymphocytes.

Resting B lymphocytes are poor APCs and are unable to induce strong T-cell immunity [20]. B cells can be activated by a variety of stimuli to acquire immunostimulatory capacity, including B-cell receptor (BCR) binding to antigen and toll-like receptor-mediated signals. However, signals transmitted via CD40 have consistently been found to be the most potent inducer of many features of potent APCs [2]. Several strategies have been investigated to exploit CD40-CD40L interaction for the generation of antigen-presenting B cells (summarized in Table 1 for human B cells ) [reviewed in 21]. These include the usage of recombinant soluble CD40L proteins [22-25], triggering CD40 with agonistic monoclonal CD40 antibodies [26, 27], and CD40L-expressing feeder cells [28-30]. A number of factors affect the extent of B-cell activation by CD40-mediated signals. For instance, the effect of anti-CD40 antibodies on B-cell activation is determined by the exact location of their binding to CD40 [5]. Another factor that crucially determines the extent of B cell activation is the degree of CD40 crosslinking. It has long been established that optimal bioactivity is only observed when using a multimerized form of the CD40L homotrimer, thus allowing clustering on the cell surface [31-33]. Clustering of the CD40L is not elicited by monoclonal anti-CD40 antibodies, thus only inducing activation, but not proliferation of B cells [31-33]. CD40L- expressing feeder cells naturally provide a multimerized form of the CD40L, but to avoid xenogeneic components in clinical products recombinant soluble CD40L is the preferred choice for a clinical application of B cells.

Table 1.

Methods for generating human antigen-presenting B cells

Methods for generating human antigen-presenting B cells
Methods for generating human antigen-presenting B cells

Typically, human peripheral blood mononuclear cells (PBMCs) or purified B cells are cultured for a period of at least 14 days in the presence of the soluble CD40L and IL-4 [22, 23], in which the addition of IL-4 is necessary for B-cell proliferation [34]. These culture conditions result in a profound polyclonal activation of B cells that leads to an approximately 20-fold expansion [15, 35, 36] and the acquisition of an antigen-presenting phenotype [15, 37, 38]. When PBMCs are used as the starting material, typically B-cell purities of more than 95% can be achieved. Throughout the culture period, B cells acquire a memory-like state that represents an intermediary stage between naïve B cells and plasma cells [39]. B cells that are stimulated for at least 3 days by the CD40L show a high expression of MHC class I and MHC class II molecules, the costimulatory markers CD80, CD83, and CD86, and the adhesion molecules CD54 and CD58, which remains stable throughout the subsequent culture period [15, 18, 35, 37, 38]. Combination of CD40L stimulation with CpG as proposed by some studies [18, 40] has no further impact on the expression of activation markers or proliferation of B cells, while additional stimulation with LPS further increases the activation of B cells [18, 40]. When normalized relative to cell size, expression levels of activation molecules on the cell surface of CD40B cells are equivalent to CD40L/IFN-γ or TNF-α-matured DCs [35].

Increased expression of MHC and costimulatory molecules on CD40B cells correlates with the acquisition of antigen-presenting functions. CD40 activation results in improved antigen processing and presentation [41], typically via the classical MHC class II pathway [18, 42], but also a distinct nonclassical, cytosolic MHC class II pathway [43]. Becker et al. [43] demonstrated that presentation of the model antigen CMV pp65 by CD40B cells was limited when using the proteasome inhibitor epoxomicin resulting in reduced T-cell activation and IFN-γ production. However, epoxomicin sensitivity was not observed in DCs, suggesting an antigen-processing mechanism unique to CD40B cells.

The ability of human CD40B cells to expand antigen-experienced CD4+ T cells, but also to prime naïve CD4+ T cells was demonstrated in several studies [15, 17, 22, 24, 26, 35, 37, 44, 45]. Lapointe et al. [37] showed that when pulsed with tumor lysates, CD40B cells expanded and activated tumor antigen-specific memory CD4+ T cells from the blood of cancer patients. Our group demonstrated that responses of naïve CD4+ T cells against MCH class II-restricted neoantigens could be induced when using CD40B cells as sole APCs [42]. In addition, expression of CD107a and CD40L was detected in CD4+ T cells early after activation with CD40B cells [46].

Human CD40B cells also cross-present antigen via MHC class I pathways and, thus, where shown to induce naïve and memory CD8+ T-cell responses [47-49]. Similar to the system used for CD4+ T cells, CD40B cells were used as APCs to expand antigen-specific CD8+ T cells from healthy donors and cancer patients [15, 35, 36, 45, 48-50]. Specific T-cell responses where not only detected against the memory antigens influenza A MP58, MART-1, and hTERT, but also the neoantigen RTpol from HIV [35], thus again demonstrating the ability of CD40B cells to induce naïve T-cell responses.

CD40B cells fulfill crucial requirements for their use as APCs in cancer immunotherapy: (1) they can be consistently generated from peripheral blood, (2) they are relatively insensitive towards tumor-derived immunosuppressive mechanisms, (3) they do not induce tolerance by themselves, and (4) they are well tolerated upon infusion in terms of toxic side effects.

From a practical view, CD40B cells offer several potential advantages over DCs. From a small amount of peripheral blood, one can usually obtain sufficient numbers (approximately 1 × 105 to 1 × 107 cells/kg body weight) of activated antigen-presenting B cells [35, 51], whereas the generation of DCs typically requires a leukapheresis [52-55]. It has been shown that this is even feasible in cancer patients [35, 51]. This aspect is particularly important considering that cancer patients typically are frequently lymphocytopenic due to the underlying disease and/or prior chemotherapy. Furthermore, the culture system for generating CD40B cells is relatively easy and inexpensive.

Tumor-derived factors mediating immunosuppression in the tumor microenvironment, such as prostaglandin E2 [56], TGF-β [57, 58], VEGF [59, 60] or IL-10 [61, 62], act in part by inhibiting DC differentiation, maturation, trafficking, and antigen presentation [62, 63]. Therefore, one might suppose that they have similar effects on antigen-presenting B cells. However, activated B cells turned out to be relatively resistant to inhibition by tumor-associated immunosuppressive molecules. In vitro, neither migration nor activation of CD40B cells was inhibited by these immunosuppressive factors, nor did they influence the ability of CD40B cells to induce proliferation of CD4+ or CD8+ T cells [64]. TGF-β and VEGF had no effect on the proliferation of CD40B cells, while IL-10 even increased their expansion. On the contrary, TGF-β actually enhances BCR-mediated antigen presentation [65]. Concerning the induction of tolerance by administration of activated B cells, the mode of activation is of considerable importance. While human B cells that were activated by bacterial stimuli induced anergy and apoptosis of CD4+ T cells in an IL-2-dependent manner [66], CD40B cells were shown to activate T cells in the presence of IL-2 besides the fact that they express CD25 [37, 44, 67]. Toxic side effects of CD40B-cell administration were not observed in in vivo in studies with mice or dogs. Wild-type mice received autologous CD40B cells in different injection routes (intravenous, subcutaneous, and intraperitoneal) and two different high concentrations (40 × 106 and 40 × 107 cells/kg). Body weight and survival remained unchained under all tested conditions. No abnormal lymphocytic infiltration, structural tissue injury, or indications of inflammation could be detected in histological analyses of heart, lung, liver, spleen, and kidney [68]. These results are in line with a study where administration of RNA-loaded CD40B cells was well tolerated by dogs with non-Hodgkin’s lymphoma and no long-term complications were observed in the follow-up [69].

Only few studies investigated antigen presentation by CD40B cells or the influence of their administration on tumor growth in vivo (summarized in Table 2). Sorenmo et al. [69] published results of a study using tumor RNA-loaded CD40B cells as cellular adjuvant in dogs with non-Hodgkin’s lymphoma. The authors reported positive specific immune responses as detected by IFN-γ ELISPOTs, but could not detect a statistically significant correlation between the immunological response and the clinical outcome. However, they detected a significant improvement in the rate of durable second remission and survival between vaccinated and nonvaccinated groups. Since dogs are a widely accepted animal model to evaluate safety and efficacy before proceeding to a clinical trial, this study was an important step towards a clinical application of CD40B cells.

Table 2.

Preclinical and clinical studies involving activated B cells

Preclinical and clinical studies involving activated B cells
Preclinical and clinical studies involving activated B cells

More promising results in terms of cancer treatment were reported in mice. Vaccination of wild-type mice with LCMV-antigen pulsed CD40B cells, but not LPS-activated B cells, significantly reduced growth of LL-LCMV subcutaneous tumors [70]. In two studies, which applied RNA-transfected or OVA antigen-pulsed CD40B cells in a therapeutic setting, treatment did not result in delayed tumor growth of B16.F10 melanomas or E.G7 lymphomas, respectively [71, 72]. In two studies, B cells were isolated from tumor-draining lymph nodes (TDLN) of wild-type mice with MCA205, D5G6, or 4T1 tumors [73, 74]. After activation with anti-CD40 antibodies, they were adoptively transferred into syngeneic tumor-bearing mice. In combination with activated T cells, CD40B-cell administration resulted in the reduction of spontaneous metastases. Moreover, combining adoptive transfer of B cells with chemotherapy or total body irradiation significantly inhibited tumor growth. The generated B cells were shown to produce tumor antigen-specific IgG antibodies, indicating specificity for tumor antigens presented by B cells isolated from TDLN. However, these studies used soluble anti-CD40 antibodies for the activation of B cells, which was demonstrated to result in weaker CD40 stimulation than activation by CD40L-expressing feeder cells [21, 31]. When using CD40L-expressing feeder cells for activation, vaccination with tumor antigen-pulsed CD40B cells before B16 melanomas or E.G7 lymphomas were injected [68] resulted in significantly delayed growth in both tumor models. The rate of tumor control by CD40B cell vaccination was comparable to that induced by DCs. Using tumor antigen-specific B cells for immunotherapy seems to further improve the observed antitumor efficacy. Moutai et al. [75] isolated HEL-specific B cells and stimulated them with a combination of CD40L/BAFF-expressing feeder cells, IL-4, and IL-21. Therapeutic administration of these iGC-termed B cells resulted in the regression of pulmonary metastases of HEL-expressing B16 melanomas. These results are in line with a more recent study using tumor antigen-specific CD40B cells for therapeutic treatment of EG.7 lymphoma or Panc02OVA tumor-bearing mice [76]. This study exploited the advantage of antigen-specific B cells to take up and process antigen more efficiently via the specific BCR than polyclonal B cells do via BCR-independent mechanisms such as pinocytosis [77]. Antigen-specific B cells more efficiently induced antigen-specific T-cell responses in vitro and in vivo than polyclonal CD40B cells, subsequently resulting in complete remission in 60% of mice [76]. In addition, B cells were differentiated into antibody-secreting plasma cells supporting the antitumor immune response induced by CD40B cells.

The preclinical experiments described above provide a strong rational for the clinical application of CD40B cells as a cellular cancer vaccine. The proof-of-principle studies in several distinct murine cancer models and the more genetically diverse canine tumors demonstrate the potential of B cell-based cancer vaccines for the therapeutic treatment of established tumors. Apart from the above-mentioned clinical study of a CD40-activated B cell vaccine by Biagi et al. [19], there are only few clinical studies that assessed the use of B cells for cancer immunotherapy.

In two small clinical trials, B cells were used as part of a hybrid cell vaccination approach, in which allogeneic B cells from PBMCs of healthy donors were fused with autologous tumor cells. In the first study in patients with renal cell carcinoma, two complete and two partial responses were observed out of 11 patients. Most patients at least showed an initial response and the vaccination was well tolerated [78]. The second study was conducted in patients with metastatic melanoma. The vaccination with the hybrid vaccine induced T-cell relocation into the tumor nodules. Out of 16 patients, 1 complete and 1 partial remission and 5 cases of stable disease were observed. The vaccination proved to be safe as only minor side effects occurred [79].

Another study in humans using adoptive B-cell transfer rather focused on the ability of memory B cells to differentiate into plasma cells. Winkler and colleagues [80] developed a method to produce good manufacturing practice (GMP)-conforming purified human B cells for the treatment of patients after allogeneic stem cell transplantation to restore humoral immunity. They initiated a first-in-man phase I/IIa clinical trial to evaluate safety and tolerability of adoptively transferred donor B cells in a dose escalation study [81] (ClinicalTrials.gov identifier: NCT02007811). B cells were isolated under GMP-conditions from donor leukapheresis products in two separation steps in the CliniMACS® System including the depletion of CD3+ T cells followed by positive selection of CD19+ B cells. When the first results were reported (in 2016 at the ASH conference), the lower doses of 0.5 × 106, 1 × 106, and 2 × 106 B cells were well tolerated without any acute adverse reactions or chronic GvHD reactions during the observation period of 4 month. As secondary endpoints, the activity of the infused donor memory B cells was evaluated. Preliminary results suggested a significant mobilization of plasma blasts in some of the patients after revaccination with a pentavalent vaccine.

The recent development of a GMP-grade CD40-activating reagent has been one of the important steps towards the clinical testing of a CD40B cell-based cancer vaccine [22]. This B cell-activating reagent has overcome some of the problems described above with other activating reagents, i.e., xenogeneic components or poor proliferation.

Apart from the effective activation and expansion of immunostimulatory B cells, the process of loading B cells with antigen is crucial for the successful application of B cell-based cancer vaccines. BCR-mediated antigen uptake is the most efficient way of antigen acquisition and leads to highly efficient antigen processing and presentation [77, 82, 83]. Other modes of antigen uptake such as pinocytosis are less effective. Therefore, several different strategies for antigen delivery to B cells have been explored. A promising approach of antigen delivery to B cells is via the targeting of antigens to CD19 [84]. Szeto et al. [85] recently reported another interesting approach using a microfluidic device for antigen delivery to B cells through a process termed mechanoporation. In this microfluidic device, B cells are passed through narrow channels. The passage through the narrow channel causes the transient formation of pores in the B-cell membrane that facilitate the intracellular uptake of proteins from the surrounding medium.

A possible alternative to the use of polyclonal B cells that have to be loaded with tumor antigens is the isolation of B cells with tumor antigen-specific BCRs from the patients’ blood or tumor tissue. Since antigen-uptake through the BCR is highly specific and results in rapid and effective antigen processing and presentation, one can circumvent the need for antigen-loading prior to reinfusion of the B-cell vaccine. At least in mice, the use of antigen-specific CD40B cells for immunotherapy was highly efficient in inducing a strong antitumor immune response resulting in complete remission [76]. However, like the use of polyclonal B cells, this method requires the prior choice of a defined tumor antigen.

Another interesting antigen-agnostic strategy for the generation of tumor antigen-specific immunostimulatory B cells is the use of B cells that were isolated from the patient’s tumor or TDLN. In murine experiments this approach proved to be successful at inducing antitumor immunity [74]. These results are in line with an in vitro study where B cells isolated from TDLN of patients with esophageal-gastric cancer or colorectal cancer were partially specific for the tumor antigens NY-ESO-1 or CEA, respectively, and induced antigen-specific T-cell responses in vitro [76].

A possible first study with CD40B cells should strive to include the aspect of antigen specificity, to ensure that their full potential is exploited. However, since patient material is limited and isolation of antigen-specific B cells by antigen-tetramers is complex and costly to be developed in GMP-grade, isolation of the whole B-cell population from TILs offers the most promising option. This B-cell population contains B cells specific for tumor antigens, is presumably loaded with tumor antigen already, but can also be further stimulated with the CD40L [76]. Thus, a tumor entity should be chosen where TILs are easily assessable, i.e., surgery is part of the standard procedure, a possible tumor antigen for pulsing is known, and where there is a great clinical need. Manufacturing of B cells under GMP-conditions comprises no obstacles anymore after today’s experience with CAR trials [86] and B cell-adoptive transfer [81], and suitable tumor antigens for pulsing have been discovered in many solid tumor entities [87]. The whole isolation and activation process of CD40B cells in general would also be suitable for an automated manufacturing process, e.g., in the CliniMACS Prodigy (Miltenyi Biotec) [88]. The most straightforward approach would thus include isolation of B cells from TILs by CD19+ microbeads, activation and expansion with the CD40L, loading with antigen after control of the activation status, and reinjection into the patient (Fig. 1). The primary objectives would of course be the feasibility, safety, and toxicity of a CD40B-cell vaccination, but surely the induction of an immune response, persistence of transfused CD40B cells, and evidence of disease control would be equally exciting secondary objectives.

Fig. 1.

Concept of a possible CD40B-cell study. B cells can be isolated from tumor-infiltrating lymphocyte tumors (TIL) or alternatively from peripheral blood (1) by CD19 microbeads (2). After cultivation and expansion in the CD40L culture (3), the activation status is checked by determining the expression of the activation markers, CD80, CD86, MHC class I, and MHC class I, which are usually highly upregulated after CD40L stimulation (4). After pulsing with a suitable tumor antigen (5), CD40B cells are reinjected into the patient (6).

Fig. 1.

Concept of a possible CD40B-cell study. B cells can be isolated from tumor-infiltrating lymphocyte tumors (TIL) or alternatively from peripheral blood (1) by CD19 microbeads (2). After cultivation and expansion in the CD40L culture (3), the activation status is checked by determining the expression of the activation markers, CD80, CD86, MHC class I, and MHC class I, which are usually highly upregulated after CD40L stimulation (4). After pulsing with a suitable tumor antigen (5), CD40B cells are reinjected into the patient (6).

Close modal

Even though cancer vaccination has long been regarded as a promising approach for cancer immunotherapy, the sobering results of early clinical trials and the economic failure of the few approved cancer vaccines have led to reduced interest in the further development of cellular cancer vaccines. However, the current excitement about the success of immune checkpoint blockade in the treatment of a broad range of malignancies has sparked a renaissance of cancer vaccines [52]. Currently, several clinical trials are investigating the combination of DC vaccines with checkpoint inhibitors. Tumor-induced T-cell dysfunction seems to be the major immunologic mechanism that limits the ability of cellular vaccines to elicit an antitumor immune response [89, 90]. Thus, combining B-cell immunotherapy with drugs that reverse T-cell dysfunction appear to be a plausible future line of investigation.

In particular, combination of CD40B-cell vaccination and checkpoint inhibition represents a promising combination approach to further enhance the activity of B cell-based cancer immunotherapy. There are already several checkpoint inhibitors that are approved for clinical use and preclinical studies demonstrate that a dual strategy of active tumor vaccination and checkpoint blockade can overcome tumor-induced immune escape [91]. Furthermore, it can be expected that in the near future additional drugs that reverse T-cell dysfunction become available [92].

Taken together, the work of recent years that we summarized here strongly highlight the potential of B cells for immunotherapy and their applicability in a clinical setting. The most challenging obstacles for the use of CD40B cells in humans have been overcome in the meantime. The CD40-activation culture system is a versatile tool for the generation of activated B cells that can be used for immunotherapeutic purposes. The current success of chimeric antigen-receptor T cells will lead to a more widespread establishment of the infrastructure required for the clinical application of cellular therapies. In addition, technological advances such as small, automated, closed system cell manufacturing platforms that enable the decentralized “point-of-care” generation of cellular therapies will further ease the clinical testing of cellular immunotherapies such as CD40B-cell cancer vaccines [88]. Therefore, it can be expected that the near future will see the first clinical trials of B cell-based cancer vaccines. These trials will show if B cells deserve a place in the oncologist’s toolbox.

1.
Lund
FE
,
Randall
TD
.
Effector and regulatory B cells: modulators of CD4+ T cell immunity
.
Nat Rev Immunol
.
2010
Apr
;
10
(
4
):
236
47
.
[PubMed]
1474-1733
2.
Van Belle
K
,
Herman
J
,
Boon
L
,
Waer
M
,
Sprangers
B
,
Louat
T
.
Comparative In Vitro Immune Stimulation Analysis of Primary Human B Cells and B Cell Lines
.
J Immunol Res
.
2016
;
2016
:
5281823
.
[PubMed]
2314-7156
3.
Kornbluth
RS
,
Stempniak
M
,
Stone
GW
.
Design of CD40 agonists and their use in growing B cells for cancer immunotherapy
.
Int Rev Immunol
.
2012
Aug
;
31
(
4
):
279
88
.
[PubMed]
0883-0185
4.
Karpusas
M
,
Hsu
YM
,
Wang
JH
,
Thompson
J
,
Lederman
S
,
Chess
L
, et al
2 A crystal structure of an extracellular fragment of human CD40 ligand
.
Structure
.
1995
Oct
;
3
(
10
):
1031
9
.
[PubMed]
0969-2126
5.
Barr
TA
,
Heath
AW
.
Functional activity of CD40 antibodies correlates to the position of binding relative to CD154
.
Immunology
.
2001
Jan
;
102
(
1
):
39
43
.
[PubMed]
0019-2805
6.
Bishop
GA
,
Moore
CR
,
Xie
P
,
Stunz
LL
,
Kraus
ZJ
.
TRAF proteins in CD40 signaling
.
Adv Exp Med Biol
.
2007
;
597
:
131
51
.
[PubMed]
0065-2598
7.
Säemann
MD
,
Kelemen
P
,
Zeyda
M
,
Böhmig
G
,
Staffler
G
,
Zlabinger
GJ
.
CD40 triggered human monocyte-derived dendritic cells convert to tolerogenic dendritic cells when JAK3 activity is inhibited
.
Transplant Proc
.
2002
Aug
;
34
(
5
):
1407
8
.
[PubMed]
0041-1345
8.
Säemann
MD
,
Diakos
C
,
Kelemen
P
,
Kriehuber
E
,
Zeyda
M
,
Böhmig
GA
, et al
Prevention of CD40-triggered dendritic cell maturation and induction of T-cell hyporeactivity by targeting of Janus kinase 3
.
Am J Transplant
.
2003
Nov
;
3
(
11
):
1341
9
.
[PubMed]
1600-6135
9.
Danese
S
,
Sans
M
,
Fiocchi
C
.
The CD40/CD40L costimulatory pathway in inflammatory bowel disease
.
Gut
.
2004
Jul
;
53
(
7
):
1035
43
.
[PubMed]
0017-5749
10.
Kawabe
T
,
Naka
T
,
Yoshida
K
,
Tanaka
T
,
Fujiwara
H
,
Suematsu
S
, et al
The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation
.
Immunity
.
1994
Jun
;
1
(
3
):
167
78
.
[PubMed]
1074-7613
11.
Castigli
E
,
Alt
FW
,
Davidson
L
,
Bottaro
A
,
Mizoguchi
E
,
Bhan
AK
, et al
CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation
.
Proc Natl Acad Sci USA
.
1994
Dec
;
91
(
25
):
12135
9
.
[PubMed]
0027-8424
12.
Renshaw
BR
,
Fanslow
WC
 3rd
,
Armitage
RJ
,
Campbell
KA
,
Liggitt
D
,
Wright
B
, et al
Humoral immune responses in CD40 ligand-deficient mice
.
J Exp Med
.
1994
Nov
;
180
(
5
):
1889
900
.
[PubMed]
0022-1007
13.
Caux
C
,
Massacrier
C
,
Vanbervliet
B
,
Dubois
B
,
Van Kooten
C
,
Durand
I
, et al
Activation of human dendritic cells through CD40 cross-linking
.
J Exp Med
.
1994
Oct
;
180
(
4
):
1263
72
.
[PubMed]
0022-1007
14.
Banchereau
J
,
de Paoli
P
,
Vallé
A
,
Garcia
E
,
Rousset
F
.
Long-term human B cell lines dependent on interleukin-4 and antibody to CD40
.
Science
.
1991
Jan
;
251
(
4989
):
70
2
.
[PubMed]
0036-8075
15.
Schultze
JL
,
Michalak
S
,
Seamon
MJ
,
Dranoff
G
,
Jung
K
,
Daley
J
, et al
CD40-activated human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy
.
J Clin Invest
.
1997
Dec
;
100
(
11
):
2757
65
.
[PubMed]
0021-9738
16.
von Bergwelt-Baildon
M
,
Shimabukuro-Vornhagen
A
,
Popov
A
,
Klein-Gonzalez
N
,
Fiore
F
,
Debey
S
, et al
CD40-activated B cells express full lymph node homing triad and induce T-cell chemotaxis: potential as cellular adjuvants
.
Blood
.
2006
Apr
;
107
(
7
):
2786
9
.
[PubMed]
0006-4971
17.
Su
KY
,
Watanabe
A
,
Yeh
CH
,
Kelsoe
G
,
Kuraoka
M
.
Efficient Culture of Human Naive and Memory B Cells for Use as APCs
.
J Immunol
.
2016
Nov
;
197
(
10
):
4163
76
.
[PubMed]
0022-1767
18.
Mathieu
M
,
Cotta-Grand
N
,
Daudelin
JF
,
Boulet
S
,
Lapointe
R
,
Labrecque
N
.
CD40-activated B cells can efficiently prime antigen-specific naïve CD8+ T cells to generate effector but not memory T cells
.
PLoS One
.
2012
;
7
(
1
):
e30139
.
[PubMed]
1932-6203
19.
Biagi
E
,
Rousseau
R
,
Yvon
E
,
Schwartz
M
,
Dotti
G
,
Foster
A
, et al
Responses to human CD40 ligand/human interleukin-2 autologous cell vaccine in patients with B-cell chronic lymphocytic leukemia
.
Clin Cancer Res
.
2005
Oct
;
11
(
19 Pt 1
):
6916
23
.
[PubMed]
1078-0432
20.
Evans
DE
,
Munks
MW
,
Purkerson
JM
,
Parker
DC
.
Resting B lymphocytes as APC for naive T lymphocytes: dependence on CD40 ligand/CD40
.
J Immunol
.
2000
Jan
;
164
(
2
):
688
97
.
[PubMed]
0022-1767
21.
Néron
S
,
Nadeau
PJ
,
Darveau
A
,
Leblanc
JF
.
Tuning of CD40-CD154 interactions in human B-lymphocyte activation: a broad array of in vitro models for a complex in vivo situation
.
Arch Immunol Ther Exp (Warsz)
.
2011
Feb
;
59
(
1
):
25
40
.
[PubMed]
0004-069X
22.
Garcia-Marquez
MA
,
Shimabukuro-Vornhagen
A
,
Theurich
S
,
Kochanek
M
,
Weber
T
,
Wennhold
K
, et al
A multimerized form of recombinant human CD40 ligand supports long-term activation and proliferation of B cells
.
Cytotherapy
.
2014
Nov
;
16
(
11
):
1537
44
.
[PubMed]
1465-3249
23.
Jourdan
M
,
Robert
N
,
Cren
M
,
Thibaut
C
,
Duperray
C
,
Kassambara
A
, et al
Characterization of human FCRL4-positive B cells
.
PLoS One
.
2017
Jun
;
12
(
6
):
e0179793
.
[PubMed]
1932-6203
24.
Naito
M
,
Hainz
U
,
Burkhardt
UE
,
Fu
B
,
Ahove
D
,
Stevenson
KE
, et al
CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells
.
Cancer Immunol Immunother
.
2012
;
•••
:
[PubMed]
0340-7004
25.
Fournel
S
,
Wieckowski
S
,
Sun
W
,
Trouche
N
,
Dumortier
H
,
Bianco
A
, et al
C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L
.
Nat Chem Biol
.
2005
Dec
;
1
(
7
):
377
82
.
[PubMed]
1552-4450
26.
Carpenter
EL
,
Mick
R
,
Rüter
J
,
Vonderheide
RH
.
Activation of human B cells by the agonist CD40 antibody CP-870,893 and augmentation with simultaneous toll-like receptor 9 stimulation
.
J Transl Med
.
2009
Nov
;
7
(
1
):
93
.
[PubMed]
1479-5876
27.
Tu
W
,
Lau
YL
,
Zheng
J
,
Liu
Y
,
Chan
PL
,
Mao
H
, et al
Efficient generation of human alloantigen-specific CD4+ regulatory T cells from naive precursors by CD40-activated B cells
.
Blood
.
2008
Sep
;
112
(
6
):
2554
62
.
[PubMed]
0006-4971
28.
Yoon
SH
,
Cho
HI
,
Kim
TG
.
Activation of B cells using Schneider 2 cells expressing CD40 ligand for the enhancement of antigen presentation in vitro
.
Exp Mol Med
.
2005
Dec
;
37
(
6
):
567
74
.
[PubMed]
1226-3613
29.
Schultze
JL
,
Cardoso
AA
,
Freeman
GJ
,
Seamon
MJ
,
Daley
J
,
Pinkus
GS
, et al
Follicular lymphomas can be induced to present alloantigen efficiently: a conceptual model to improve their tumor immunogenicity
.
Proc Natl Acad Sci USA
.
1995
Aug
;
92
(
18
):
8200
4
.
[PubMed]
0027-8424
30.
Ivanov
R
,
Aarts
T
,
Hagenbeek
A
,
Hol
S
,
Ebeling
S
.
B-cell expansion in the presence of the novel 293-CD40L-sCD40L cell line allows the generation of large numbers of efficient xenoantigen-free APC
.
Cytotherapy
.
2005
;
7
(
1
):
62
73
.
[PubMed]
1465-3249
31.
Fanslow
WC
,
Srinivasan
S
,
Paxton
R
,
Gibson
MG
,
Spriggs
MK
,
Armitage
RJ
.
Structural characteristics of CD40 ligand that determine biological function
.
Semin Immunol
.
1994
Oct
;
6
(
5
):
267
78
.
[PubMed]
1044-5323
32.
Morris
AE
,
Remmele
RL
 Jr
,
Klinke
R
,
Macduff
BM
,
Fanslow
WC
,
Armitage
RJ
.
Incorporation of an isoleucine zipper motif enhances the biological activity of soluble CD40L (CD154)
.
J Biol Chem
.
1999
Jan
;
274
(
1
):
418
23
.
[PubMed]
0021-9258
33.
Haswell
LE
,
Glennie
MJ
,
Al-Shamkhani
A
.
Analysis of the oligomeric requirement for signaling by CD40 using soluble multimeric forms of its ligand, CD154
.
Eur J Immunol
.
2001
Oct
;
31
(
10
):
3094
100
.
[PubMed]
0014-2980
34.
Tadmori
W
,
Lee
HK
,
Clark
SC
,
Choi
YS
.
Human B cell proliferation in response to IL-4 is associated with enhanced production of B cell-derived growth factors
.
J Immunol
.
1989
Feb
;
142
(
3
):
826
32
.
[PubMed]
0022-1767
35.
von Bergwelt-Baildon
MS
,
Vonderheide
RH
,
Maecker
B
,
Hirano
N
,
Anderson
KS
,
Butler
MO
, et al
Human primary and memory cytotoxic T lymphocyte responses are efficiently induced by means of CD40-activated B cells as antigen-presenting cells: potential for clinical application
.
Blood
.
2002
May
;
99
(
9
):
3319
25
.
[PubMed]
0006-4971
36.
Wiesner
M
,
Zentz
C
,
Mayr
C
,
Wimmer
R
,
Hammerschmidt
W
,
Zeidler
R
, et al
Conditional immortalization of human B cells by CD40 ligation
.
PLoS One
.
2008
Jan
;
3
(
1
):
e1464
.
[PubMed]
1932-6203
37.
Lapointe
R
,
Bellemare-Pelletier
A
,
Housseau
F
,
Thibodeau
J
,
Hwu
P
,
Cells
ST
, et al
CD40-stimulated B lymphocytes pulsed with tumor antigens are effective antigen-presenting cells that can generate specific T cells
.
Cancer Res
.
2003
Jun
;
63
(
11
):
2836
43
.
[PubMed]
0008-5472
38.
Coughlin
CM
,
Vance
BA
,
Grupp
SA
,
Vonderheide
RH
.
RNA-transfected CD40-activated B cells induce functional T-cell responses against viral and tumor antigen targets: implications for pediatric immunotherapy
.
Blood
.
2004
Mar
;
103
(
6
):
2046
54
.
[PubMed]
0006-4971
39.
Upadhyay
M
,
Priya
GK
,
Ramesh
P
,
Madhavi
MB
,
Rath
S
,
Bal
V
, et al
CD40 signaling drives B lymphocytes into an intermediate memory-like state, poised between naïve and plasma cells
.
J Cell Physiol
.
2014
Oct
;
229
(
10
):
1387
96
.
[PubMed]
0021-9541
40.
Hawkins
ED
,
Turner
ML
,
Wellard
CJ
,
Zhou
JH
,
Dowling
MR
,
Hodgkin
PD
.
Quantal and graded stimulation of B lymphocytes as alternative strategies for regulating adaptive immune responses
.
Nat Commun
.
2013
;
4
(
1
):
2406
.
[PubMed]
2041-1723
41.
Faassen
AE
,
Dalke
DP
,
Berton
MT
,
Warren
WD
,
Pierce
SK
.
Faassen a E, Dalke DP, Berton MT, Warren WD, Pierce SK: CD40-CD40 ligand interactions stimulate B cell antigen processing
.
Eur J Immunol
.
1995
;
25
(
12
):
3249
55
. 0014-2980
42.
von Bergwelt-Baildon
M
,
Schultze
JL
,
Maecker
B
,
Menezes
I
,
Nadler
LM
.
Correspondence re R. Lapointe et al., CD40-stimulated B lymphocytes pulsed with tumor antigens are effective antigen-presenting cells that can generate specific T cells. Cancer Res 2003;63:2836-43
.
Cancer Res
.
2004
Jun
;
64
(
11
):
4055
6
.
[PubMed]
0008-5472
43.
Becker
HJ
,
Kondo
E
,
Shimabukuro-Vornhagen
A
,
Theurich
S
,
von Bergwelt-Baildon
MS
.
Processing and MHC class II presentation of exogenous soluble antigen involving a proteasome-dependent cytosolic pathway in CD40-activated B cells
.
Eur J Haematol
.
2015
;
•••
:
[PubMed]
0902-4441
44.
Fujiwara
H
,
Melenhorst
JJ
,
El Ouriaghli
F
,
Kajigaya
S
,
Grube
M
,
Sconocchia
G
, et al
In vitro induction of myeloid leukemia-specific CD4 and CD8 T cells by CD40 ligand-activated B cells gene modified to express primary granule proteins
.
Clin Cancer Res
.
2005
Jun
;
11
(
12
):
4495
503
.
[PubMed]
1078-0432
45.
Shimabukuro-Vornhagen
A
,
Zoghi
S
,
Liebig
TM
,
Wennhold
K
,
Chemitz
J
,
Draube
A
, et al
Inhibition of protein geranylgeranylation specifically interferes with CD40-dependent B cell activation, resulting in a reduced capacity to induce T cell immunity
.
J Immunol
.
2014
Nov
;
193
(
10
):
5294
305
.
[PubMed]
0022-1767
46.
Theurich
S
,
Malcher
J
,
Becker
HJ
,
Chemnitz
JM
,
Liebig
TM
,
Shimabukuro-Vornhagen
A
, et al
Activated primary human B cells efficiently induce early CD40L and CD107a expression in CD4+ T cells
.
Blood
.
2011
Nov
;
118
(
22
):
5979
80
.
[PubMed]
0006-4971
47.
Zheng
J
,
Liu
Y
,
Qin
G
,
Chan
PL
,
Mao
H
,
Lam
KT
, et al
Efficient induction and expansion of human alloantigen-specific CD8 regulatory T cells from naive precursors by CD40-activated B cells
.
J Immunol
.
2009
Sep
;
183
(
6
):
3742
50
.
[PubMed]
0022-1767
48.
Zentz
C
,
Wiesner
M
,
Man
S
,
Frankenberger
B
,
Wollenberg
B
,
Hillemanns
P
, et al
Activated B cells mediate efficient expansion of rare antigen-specific T cells
.
Hum Immunol
.
2007
Feb
;
68
(
2
):
75
85
.
[PubMed]
0198-8859
49.
Wu
C
,
Liu
Y
,
Zhao
Q
,
Chen
G
,
Chen
J
,
Yan
X
, et al
Soluble CD40 ligand-activated human peripheral B cells as surrogated antigen presenting cells: A preliminary approach for anti-HBV immunotherapy
.
Virol J
.
2010
Dec
;
7
(
1
):
370
.
[PubMed]
1743-422X
50.
Wan
Y
,
Ma
X
,
Li
X
,
Yi
J
.
A novel immunotherapy to hepatocellular carcinoma: CD40-activated B lymphocytes transfected with AFPmRNA
.
Med Hypotheses
.
2009
Nov
;
73
(
5
):
835
7
.
[PubMed]
0306-9877
51.
Kondo
E
,
Gryschok
L
,
Klein-Gonzalez
N
,
Rademacher
S
,
Weihrauch
MR
,
Liebig
T
, et al
CD40-activated B cells can be generated in high number and purity in cancer patients: analysis of immunogenicity and homing potential
.
Clin Exp Immunol
.
2009
Feb
;
155
(
2
):
249
56
.
[PubMed]
0009-9104
52.
Garg
AD
,
Coulie
PG
,
Van den Eynde
BJ
,
Agostinis
P
.
Integrating Next-Generation Dendritic Cell Vaccines into the Current Cancer Immunotherapy Landscape
.
Trends Immunol
.
2017
Aug
;
38
(
8
):
577
93
.
[PubMed]
1471-4906
53.
Nava
S
,
Dossena
M
,
Pogliani
S
,
Pellegatta
S
,
Antozzi
C
,
Baggi
F
, et al
An optimized method for manufacturing a clinical scale dendritic cell-based vaccine for the treatment of glioblastoma
.
PLoS One
.
2012
;
7
(
12
):
e52301
.
[PubMed]
1932-6203
54.
Nguyen
XD
,
Eichler
H
,
Sucker
A
,
Hofmann
U
,
Schadendorf
D
,
Klüter
H
.
Collection of autologous monocytes for dendritic cell vaccination therapy in metastatic melanoma patients
.
Transfusion
.
2002
Apr
;
42
(
4
):
428
32
.
[PubMed]
0041-1132
55.
Svensson
A
,
Adamson
L
,
Pisa
P
,
Petersson
M
,
Hansson
M
.
Monocyte enriched apheresis for preparation of dendritic cells (DC) to be used in cellular therapy
.
Transfus Apheresis Sci
.
2005
Oct
;
33
(
2
):
165
73
.
[PubMed]
1473-0502
56.
Harizi
H
,
Grosset
C
,
Gualde
N
.
Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes
.
J Leukoc Biol
.
2003
Jun
;
73
(
6
):
756
63
.
[PubMed]
0741-5400
57.
Yang
L
.
TGFbeta, a potent regulator of tumor microenvironment and host immune response, implication for therapy
.
Curr Mol Med
.
2010
Jun
;
10
(
4
):
374
80
.
[PubMed]
1566-5240
58.
Geissmann
F
,
Revy
P
,
Regnault
A
,
Lepelletier
Y
,
Dy
M
,
Brousse
N
, et al
TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells
.
J Immunol
.
1999
Apr
;
162
(
8
):
4567
75
.
[PubMed]
0022-1767
59.
Johnson
BF
,
Clay
TM
,
Hobeika
AC
,
Lyerly
HK
,
Morse
MA
.
Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy
.
Expert Opin Biol Ther
.
2007
Apr
;
7
(
4
):
449
60
.
[PubMed]
1471-2598
60.
Gabrilovich
DI
,
Chen
HL
,
Girgis
KR
,
Cunningham
HT
,
Meny
GM
,
Nadaf
S
, et al
Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells
.
Nat Med
.
1996
Oct
;
2
(
10
):
1096
103
.
[PubMed]
1078-8956
61.
Sabat
R
,
Grütz
G
,
Warszawska
K
,
Kirsch
S
,
Witte
E
,
Wolk
K
, et al
Biology of interleukin-10
.
Cytokine Growth Factor Rev
.
2010
Oct
;
21
(
5
):
331
44
.
[PubMed]
1359-6101
62.
Steinbrink
K
,
Jonuleit
H
,
Müller
G
,
Schuler
G
,
Knop
J
,
Enk
AH
.
Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells
.
Blood
.
1999
Mar
;
93
(
5
):
1634
42
.
[PubMed]
0006-4971
63.
Gabrilovich
D
.
Mechanisms and functional significance of tumour-induced dendritic-cell defects
.
Nat Rev Immunol
.
2004
Dec
;
4
(
12
):
941
52
.
[PubMed]
1474-1733
64.
Shimabukuro-Vornhagen
A
,
Draube
A
,
Liebig
TM
,
Rothe
A
,
Kochanek
M
,
von Bergwelt-Baildon
MS
.
The immunosuppressive factors IL-10, TGF-β, and VEGF do not affect the antigen-presenting function of CD40-activated B cells
.
J Exp Clin Cancer Res
.
2012
May
;
31
(
1
):
47
.
[PubMed]
0392-9078
65.
Arai
C
,
Ichijo
T
,
Tanaka
Y
,
Okada
Y
,
Umeda
M
,
Uchida
T
, et al
Selective enhancement of B cell antigen receptor-mediated antigen presentation by treatment with transforming growth factor-beta
.
Eur J Immunol
.
2003
Jul
;
33
(
7
):
1806
15
.
[PubMed]
0014-2980
66.
Tretter
T
,
Venigalla
RK
,
Eckstein
V
,
Saffrich
R
,
Sertel
S
,
Ho
AD
, et al
Induction of CD4+ T-cell anergy and apoptosis by activated human B cells
.
Blood
.
2008
Dec
;
112
(
12
):
4555
64
.
[PubMed]
0006-4971
67.
Shimabukuro-Vornhagen
A
,
Kondo
E
,
Liebig
T
,
von Bergwelt-Baildon
M
.
Activated human B cells: stimulatory or tolerogenic antigen-presenting cells?
Blood
.
2009
Jul
;
114
(
3
):
746
7
.
[PubMed]
0006-4971
68.
Wennhold
K
,
Weber
TM
,
Thelen
M
,
Garcia-Marquez
M
,
Chakupurakal
G
,
Klein-Gonzalez
N
, et al
CD40-activated B cells induce anti-tumor immunity in vivo
.
Oncotarget
.
2016
;
•••
:
[PubMed]
1949-2553
69.
Sorenmo
KU
,
Krick
E
,
Coughlin
CM
,
Overley
B
,
Gregor
TP
,
Vonderheide
RH
, et al
CD40-activated B cell cancer vaccine improves second clinical remission and survival in privately owned dogs with non-Hodgkin’s lymphoma
.
PLoS One
.
2011
;
6
(
8
):
e24167
.
[PubMed]
1932-6203
70.
Ritchie
DS
,
Yang
J
,
Hermans
IF
,
Ronchese
F
.
B-Lymphocytes activated by CD40 ligand induce an antigen-specific anti-tumour immune response by direct and indirect activation of CD8(+) T-cells
.
Scand J Immunol
.
2004
Dec
;
60
(
6
):
543
51
.
[PubMed]
0300-9475
71.
Lee
J
,
Dollins
CM
,
Boczkowski
D
,
Sullenger
BA
,
Nair
S
.
Activated B cells modified by electroporation of multiple mRNAs encoding immune stimulatory molecules are comparable to mature dendritic cells in inducing in vitro antigen-specific T-cell responses
.
Immunology
.
2008
Oct
;
125
(
2
):
229
40
.
[PubMed]
0019-2805
72.
Guo
S
,
Xu
J
,
Denning
W
,
Hel
Z
.
Induction of protective cytotoxic T-cell responses by a B-cell-based cellular vaccine requires stable expression of antigen
.
Gene Ther
.
2009
Nov
;
16
(
11
):
1300
13
.
[PubMed]
0969-7128
73.
Li
Q
,
Lao
X
,
Pan
Q
,
Ning
N
,
Yet
J
,
Xu
Y
, et al
Adoptive transfer of tumor reactive B cells confers host T-cell immunity and tumor regression
.
Clin Cancer Res
.
2011
Aug
;
17
(
15
):
4987
95
.
[PubMed]
1078-0432
74.
Li
Q
,
Teitz-Tennenbaum
S
,
Donald
EJ
,
Li
M
,
Chang
AE
.
In vivo sensitized and in vitro activated B cells mediate tumor regression in cancer adoptive immunotherapy
.
J Immunol
.
2009
Sep
;
183
(
5
):
3195
203
.
[PubMed]
0022-1767
75.
Moutai
T
,
Yamana
H
,
Nojima
T
,
Kitamura
D
.
A novel and effective cancer immunotherapy mouse model using antigen-specific B cells selected in vitro
.
PLoS One
.
2014
Mar
;
9
(
3
):
e92732
.
[PubMed]
1932-6203
76.
Wennhold
K
,
Thelen
M
,
Schlößer
HA
,
Haustein
N
,
Reuter
S
,
Garcia-Marquez
M
, et al
Using Antigen-Specific B Cells to Combine Antibody and T Cell-Based Cancer Immunotherapy
.
Cancer Immunol Res
.
2017
Sep
;
5
(
9
):
730
43
.
[PubMed]
2326-6066
77.
Batista
FD
,
Neuberger
MS
.
Affinity dependence of the B cell response to antigen: a threshold, a ceiling, and the importance of off-rate
.
Immunity
.
1998
Jun
;
8
(
6
):
751
9
.
[PubMed]
1074-7613
78.
Kugler
A
,
Seseke
F
,
Thelen
P
,
Kallerhoff
M
,
Müller
GA
,
Stuhler
G
, et al
Autologous and allogenic hybrid cell vaccine in patients with metastatic renal cell carcinoma
.
Br J Urol
.
1998
Oct
;
82
(
4
):
487
93
.
[PubMed]
0007-1331
79.
Trefzer
U
,
Weingart
G
,
Chen
Y
,
Herberth
G
,
Adrian
K
,
Winter
H
, et al
Hybrid cell vaccination for cancer immune therapy: first clinical trial with metastatic melanoma
.
Int J Cancer
.
2000
Mar
;
85
(
5
):
618
26
.
[PubMed]
0020-7136
80.
Tittlbach
H
,
Schneider
A
,
Strobel
J
,
Zimmermann
R
,
Maas
S
,
Gebhardt
B
, et al
GMP-production of purified human B lymphocytes for the adoptive transfer in patients after allogeneic hematopoietic stem cell transplantation
.
J Transl Med
.
2017
Nov
;
15
(
1
):
228
.
[PubMed]
1479-5876
81.
Winkler
J
,
Tittlbach
H
,
Roesler
W
,
Strobel
J
,
Zimmermann
R
,
Maas
S
, et al
Adoptive Transfer of Purified Donor-B-Lymphocytes after Allogeneic Stem Cell Transplantation: Results from a Phase I/IIa Clinical Trial. Blood
2016
[cited 2018 Jun 22];128. Available from: http://www.bloodjournal.org/content/128/22/502?sso-checked=true
82.
Rodríguez-Pinto
D
,
Moreno
J
.
B cells can prime naive CD4+ T cells in vivo in the absence of other professional antigen-presenting cells in a CD154-CD40-dependent manner
.
Eur J Immunol
.
2005
Apr
;
35
(
4
):
1097
105
.
[PubMed]
0014-2980
83.
Liljedahl
M
,
Winqvist
O
,
Surh
CD
,
Wong
P
,
Ngo
K
,
Teyton
L
, et al
Altered antigen presentation in mice lacking H2-O
.
Immunity
.
1998
Feb
;
8
(
2
):
233
43
.
[PubMed]
1074-7613
84.
Ma
Y
,
Xiang
D
,
Sun
J
,
Ding
C
,
Liu
M
,
Hu
X
, et al
Targeting of antigens to B lymphocytes via CD19 as a means for tumor vaccine development
.
J Immunol
.
2013
Jun
;
190
(
11
):
5588
99
.
[PubMed]
0022-1767
85.
Szeto
GL
,
Van Egeren
D
,
Worku
H
,
Sharei
A
,
Alejandro
B
,
Park
C
, et al
Microfluidic squeezing for intracellular antigen loading in polyclonal B-cells as cellular vaccines
.
Sci Rep
.
2015
May
;
5
(
1
):
10276
.
[PubMed]
2045-2322
86.
Köhl
U
,
Arsenieva
S
,
Holzinger
A
,
Abken
H
.
CAR T Cells in Trials: Recent Achievements and Challenges that Remain in the Production of Modified T Cells for Clinical Applications
.
Hum Gene Ther
.
2018
May
;
29
(
5
):
559
68
.
[PubMed]
1043-0342
87.
Finn
OJ
.
Human Tumor Antigens Yesterday, Today, and Tomorrow
.
Cancer Immunol Res
.
2017
May
;
5
(
5
):
347
54
.
[PubMed]
2326-6066
88.
Mock
U
,
Nickolay
L
,
Philip
B
,
Cheung
GW
,
Zhan
H
,
Johnston
IC
, et al
Automated manufacturing of chimeric antigen receptor T cells for adoptive immunotherapy using CliniMACS prodigy
.
Cytotherapy
.
2016
Aug
;
18
(
8
):
1002
11
.
[PubMed]
1465-3249
89.
Saxena
M
,
Bhardwaj
N
.
Re-Emergence of Dendritic Cell Vaccines for Cancer Treatment
.
Trends Cancer
.
2018
Feb
;
4
(
2
):
119
37
.
[PubMed]
2405-8033
90.
Thommen
DS
,
Schumacher
TN
.
T Cell Dysfunction in Cancer
.
Cancer Cell
.
2018
Apr
;
33
(
4
):
547
62
.
[PubMed]
1535-6108
91.
Duraiswamy
J
,
Kaluza
KM
,
Freeman
GJ
,
Coukos
G
.
Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors
.
Cancer Res
.
2013
Jun
;
73
(
12
):
3591
603
.
[PubMed]
0008-5472
92.
Zarour
HM
.
Reversing T-cell Dysfunction and Exhaustion in Cancer
.
Clin Cancer Res
.
2016
Apr
;
22
(
8
):
1856
64
.
[PubMed]
1078-0432

K.W. and A.S.-V. contributed equally to this work.

Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.