Page 310 - Hematology_ Basic Principles and Practice ( PDFDrive )

258 Part III Immunologic Basis of Hematology

transfected for immunostimulatory molecules, such as cytokine genes delivered either IT or systemically. The rationale is that they destroy
(e.g., IL-2, IL-12), or inhibitory small interfering RNA for molecules cancer cells, making them available to be recognized by the immune
dampening DC activation (e.g., suppressor of cytokine signaling 1 system. They can be engineered to prevent replication in normal cells.
[SOCS1]). The herpes simplex virus (HSV)-based product talimogene laher-
The first U.S. Food and Drug Administration–approved, cell-based parepvec (T-VEC), which is an HSV-engineered oncolytic virus that
antitumor vaccine, Sipuleucel-T (Dendreon, Seattle, WA), compris- also expresses GM-CSF (to attract and differentiate DCs) improved
ing a partially enriched preparation of blood APCs pulsed with a the durable response rate in advanced unresectable melanoma (16.3%
recombinant fusion protein of human prostatic acid phosphatase and in the treated group versus 2.1% in subjects receiving only GM-CSF;
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GM-CSF and given intravenously, is approved for the treatment of p < 0.001). T-VEC is now being tested in combination with ipilim-
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castration-resistant prostate cancer. The vaccine resulted in modest umab or pembrolizumab (anti-PD-1), and early results of the T-VEC
improvement in overall survival, indicating a need to further improve and ipilimumab trial appear to be showing synergistic activity. T-VEC
DC-based vaccines in the clinic. Several trials tested over the past two has now been approved for the treatment of unresectable melanoma.
decades have established that DC vaccines are safe, and evidence of Anticancer vaccination can be used in synergy with chemotherapy
their immunogenicity is not in dispute. However, there remains no and radiotherapy. The rationale is that chemotherapy and radiotherapy
standardized protocol for their ex vivo manipulation. The optimal trigger tumor cell death, which provides a source of tumor antigens to
source of DCs (monocyte-derived, circulating differentiated DCs, DCs while inducing exposure of immunogenic molecules on tumor
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DCs derived from CD34 progenitors), antigen loading, maturation cells (Fig. 23.4). Thus anthracycline-treated tumor cells expose the
stimulus, and route of delivery are still in contention, and, until ER chaperones calreticulin and ERp57 because of induction of an ER
appropriately compared, it is difficult to reconcile studies that have stress response and potentiate dying tumor cell phagocytosis. Death
addressed these variables. 212 of tumor cells as a result of radiotherapy is also accompanied by
To improve immunogenicity, DC vaccines are being manipulated release of nonhistone chromatin-binding nuclear protein HMGB1,
in novel ways. For example, they are being loaded through electro- which can trigger TLR4 and, in response to taxanes, ATP, which,
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poration with RNA that encodes tumor-associated antigens or upon binding to P2RX7 on APCs, potentiates inflammasome activa-
costimulatory molecules (CD40L, CD70, and constitutively active tion and IL-1β release. Finally, cyclophosphamide can cause, through
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TLR4) or delivered directly into lymph nodes to improve access to release of tumor-associated nucleic acids, induction of type I IFN.
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secondary lymphoid organs or even intratumorally. Because skin Increased uptake of tumor antigen in the context of maturation
injections of DCs result in just a small percentage of cells migrating signals strongly enhances cross-presentation and cross-priming of
to draining nodes, investigators are preconditioning the vaccine site tumor antigens by DCs.
to stimulate local production to enhance their migration to draining Thus far, DC vaccines have not met the desired endpoints in clini-
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lymph nodes. DC–tumor cell hybrids are also being explored as cal studies (i.e., tumor regression) in the majority of patients, despite
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immunogens. With newer methods to readily expand CD34 HPCs clear evidence that DC vaccination can induce measurable cellular or
from blood, the concept of using these progenitors to derive large humoral immune responses in patients with cancer. 223–226 It is likely
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numbers of more immunogenic DC subsets (e.g., CD141 DCs) is that, to achieve significant clinical responses upon vaccination for
a future target. The ability to use the CRISPR (clustered regularly cancer, combining DC vaccination with other strategies will improve
interspaced short palindromic repeats)/Cas9 system for gene editing the therapeutic outcome. For example, some strategies are aimed
may further facilitate manipulation of DCs, such as to prevent at depleting or inactivating Tregs (using a toxin targeting CD25,
expression of inhibitory molecules or cytokines to improve their a molecule expressed by Tregs, or cyclophosphamide), alleviating
effectiveness in vivo or to preferentially drive CTL differentiation. T-cell anergy (using antagonistic CTLA-4 or PD-1), and differentiat-
Flt3L is being used to systemically increase the pre-cDC pool and/ ing myeloid suppressor cells into nonimmunosuppressive cells (by
or to target DCs in vivo using cancer antigens fused to monoclonal injection of RA derivative ATRA [all-trans retinoic acid]), injection
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antibodies targeting DC surface receptors (e.g., DEC-205). This of common γ-chain cytokines such as IL-7, which have potent
approach is also being tested in combination with decitabine and effects on T-cell survival and function, or adoptive immunotherapy
the IDO inhibitor INCB024360, which suppresses Treg generation. of in vitro activated T cells. 227,228 Irradiation of the tumor tissue
Other receptor targets under consideration for DC targeting include conditions it for enhanced migration of APCs and T cells, augments
CD40, mannose receptor, DC-SIGN, DCIR, Clec9A, and XCR1. MHC class I expression on tumor cells, and induces apoptotic cell
Indirect approaches to targeting DCs include the use of vaccines death, thus augmenting delivery of tumor antigens to DCs. 229–231
that employ tumor cells expressing GM-CSF (GVAX), which are The identification of specific surface receptors regulating DC–T-
demonstrating evidence of immunogenicity and clinical activity in cell interaction and T-cell activation and differentiation allowed use
vivo, viral or bacterial vectors that can infect and mDCs (vaccinia of targeting antibodies functioning as immune modulators. Thus
virus, Listeria monocytogenes constructs), implantable scaffolds that agonistic antibodies targeting glucocorticoid-induced TNF receptor
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recruit DCs through expression of TLR agonists and GM-CSF, (GITR), OX40, CD137, or CD40 or cytokines potently enhanc-
and exosomes derived from DCs (dexosomes). ing cytotoxic T-cell responses, such as IL-15, can be harnessed to
Altogether, DC interventions have clear immunologic and in enhance vaccine-induced antitumor immune responses. Researchers
some cases small clinical impact. Beyond Sipuleucel-T, however, no in ongoing trials are testing DCs in combination with antibodies
other DC-based vaccine has reached approval in the clinic. The that inhibit checkpoint molecules (e.g., CTLA-4, PD-1), radiation,
outcomes of phase III trials that are testing DCs’ immunogenicity in cytokines (IL-7), and drugs (e.g., enzulutamide [for prostate cancer]
renal cancer and glioblastoma multiforme are pending. Ultimately, and agents that reduce Tregs [cyclophosphamide, temozolomide]),
DCs may be more effective when given as immune prevention after among other strategies.
tumor resection or in the neoadjuvant setting, where early studies In the authors’ opinion, DC immunotherapy will be most effica-
suggest they may have impact. 217 cious when coadministered with one or more additional interventions
Novel approaches to target DCs in situ include the concept of IT and when the tumor burden is low. The timing of vaccination is
vaccination. IT injection of the CpG oligonucleotide (PF-3512676) probably also crucial, and frequent immunizations may dramatically
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in low-grade B-cell lymphoma, thus targeting TLR9 on pDCs and improve clinical efficacy. In the setting of HIV infection, a recent
B cells, has led to complete and partial clinical in several patients study of a small group of chronically infected individuals showed
with induction of tumor-specific CD8 T-cell responses. 218,219 Tumor that vaccination with DCs loaded with chemically inactivated virus
regression was observed in injected and distant tumor sites. IT allows stabilization and even suppression of viral load for an extended
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approaches are being tested with other immune modulators, such period of time without any other treatment. Vaccination with DCs
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as poly(I:C), a TLR3 and MDA5 agonist, and in combination holds great promise in cancer and infectious diseases, but its potential
with antibodies that target checkpoint molecules, such as CTLA-4 is likely to be best exploited in combination with other strategies
and PD-1. Oncolytic viruses are gaining momentum when they are manipulating other arms of the immune system.