Journal for immunotherapy of cancer impact

The Department of Diagnostic Imaging, The Warren Alpert Medical School of Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02903, USA.
A form of T cell or B cell inactivation in which the cell remains alive but cannot be activated to execute an immune response. The implantation of radioactive pellets, which are approximately the size of a grain of rice, into the tissue that is being treated for cancer. Elimination of T cells or B cells that have a high avidity for self antigens, either by negative selection during lymphocyte development or by FAS ligand-mediated destruction in the peripheral blood. A form of tissue necrosis in which injury denatures structural proteins and enzymes, thereby prohibiting proteolysis of dead cells. Iodized poppyseed oil, which has been used for more than a century as a radiographic contrast agent. The application of radiation beams that are shaped to match the tumour to more precisely target it.
A procedure whereby chemotherapy is injected directly into the arterial supply of the tumour, and embolic agents are administered that cut off its blood supply. Surgical instruments with a three-sided cutting point enclosed in a hollow cylinder that is used to place other devices into the blood vessel or body cavity that it enters.
Andrea Miyahira is currently a post-doctoral fellow at the Beckman Research Institute of the City of Hope, in Duarte, CA. Dendritic-cell (DC) differentiation is a complex multi-step genetic programme that is regulated by distinct signals. We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you.
Checkpoint blocking antibodies targeting regulatory molecules on T cells such as CTLA-4 and PD-1 have reinvigorated the field of cancer immunotherapy. Immunotherapy is poised to assume a more central role in the treatment of a variety of cancer types. This story begins with the success of translating the basic immunologic observation that CTLA-4 is a negative regulator of T cells into the preclinical observation that blockade of CTLA-4 can have potent anti-tumor activity in mouse models, and then into the subsequent clinical trials that tested this concept in a population of patients with advanced melanoma (1–7). Likewise, for PD-1, a firm foundation of basic immunologic studies, including mouse models of chronic infectious disease, helped characterize PD-1 along with its ligands PD-L1 and PD-L2, as negative regulators of effector T cell function that act predominantly in the tissue where the immune response in ongoing (10). Strong preclinical rationale for the clinical evaluation of combined CTLA-4 and PD-1 pathway blockade was provided by basic immunologic observations, which supported the notion that CTLA-4 and PD-1 are non-redundant pathways for the regulation of T cell responses, suggesting that the combination could have additive or synergistic potential. The first study of combined checkpoint blockade tested the combination of ipilimumab with nivolumab in the treatment of advanced melanoma (Table 1) (30, 31). As in prior studies of checkpoint blocking antibodies, the durability of responses was a notable virtue of this combination. Toxicities associated with CTLA-4 or PD-1 pathway blockade have been well described and include a constellation of tissue-specific inflammatory events that appear consistent with the known immune-activating mechanism of action for these agents.
The search for biomarkers that might help select a patient population most likely to benefit from checkpoint blockade is an area of ongoing research, but to date, no clinically applicable biomarker appropriate for patient selection has been identified. PD-L1 tumor expression as a potential biomarker was explored in the present study for patients treated with the concurrent combination of ipilimumab and nivolumab (cohorts 1–3, 2A) and for those who received nivolumab monotherapy sequenced after prior ipilimumab (cohorts 6 and 7) (30). Appropriate caution should be applied to the results of a small, non-randomized phase 1 study conducted at a small number of academic sites. Both combination arms were found to be safe, and no grade 5 treatment related AEs were reported.
Clinical activity for the combination of nivolumab and ipilimumab was relatively modest across cohorts in this small study of NSCLC, with an aggregate ORR of 16%. The combination of ipilimumab and nivolumab is just the first step in exploring the utility of combined checkpoint blockade.
The combination of radiation therapy and immunotherapy holds particular promise as a strategy for cancer therapeutics.
Radiation is often considered immunosuppressive, an activity that is most likely a result of the complex interplay of hormesis and the abscopal effect.
Many clinical trials exploring the use of radiation and vaccines in the treatment of cancer are currently underway. On their own, tumor cells do not generate potent antitumor immune responses due to their inefficient expression of molecules important for antigen processing and presentation. FIGURE 1Antigen Release From Dying Tumor Cells Can Activate Immune Responses—Irradiation induces death of cancer cells.
Antigens released by dying tumor cells can activate the immune system to induce immunogenic cancer cell death, thus contributing to the eradication of residual tumor cells (Figure 1).[1,4,5] In order to induce this immune response, dying tumor cells need to provide two signals for DCs.
The immunologic consequences of radiation therapy–induced tumor-cell death are thus twofold: providing a source of tumor antigens for presentation by circulating DCs and providing “danger” signals for DC activation (Figure 1). FIGURE 2Irradiation Modulates Tumor-Cell Phenotype and Increases Immune Recognition—Irradiation can cause (a) upregulation of chemokines and adhesion molecules, providing signals for T cells to come to areas of tumor, (b) upregulation of major histocompatibility complex (MHC) molecules and tumor-associated antigens, making it easier for T cells to recognize tumor, and (c) upregulation of Fas and downregulation of regulatory T cells, making it easier for cytotoxic tumor-specific T cells to kill tumor.
Neoplastic cells may evade the adaptive immune system by altering expression of specific molecules such as tumor-associated antigens (TAAs) or MHC molecules.
MHC class I is responsible for direct presentation of tumor antigen peptides to cytotoxic T lymphocytes (CTLs) via peptide-MHC complexes.
During the latter phase of ionizing radiation (> 4 hours after exposure) the mammalian target of rapamycin (mTOR) pathway is activated, resulting in translation of proteins and increased generation of peptides from the RDPs of these new proteins.
FIGURE 3Multiple Mechanisms of Synergy of Radiation Therapy and Immunotherapy—See text for details. Radiation has also been shown to alter the cell-surface expression of a variety of immunomodulatory molecules.
Microarray analysis of gene-expression changes revealed that many additional genes had been modulated by irradiation. In examining the potential mechanisms of the combination of radiation therapy with immunotherapy, it has recently been reported in murine systems that lymphodepletion from 5 Gy total-body irradiation followed by adoptive transfer of tumor-specific T cells resulted in significantly improved antitumor activity.[20] There, Gattinoni et al found that the irradiation removed endogenous cell populations that acted as sinks for the needed interleukin (IL)-7 and IL-15 cytokine supporting the tumor-reactive T cells. Another factor being examined is the removal of regulatory T cells (Tregs) by irradiation[4,21] and the role of TLR4 from radiation-injured gut on the activation of immune cells.[22,23] These mechanisms are also being seen in patients.
Recent clinical studies suggest that adoptive transfer of donor-derived natural killer (NK) cells may improve clinical outcome in hematological malignancies and some solid tumors by direct anti-tumor effects as well as by reduction of graft versus host disease (GVHD). The critical role of natural killer (NK) cells in the defense against cancer and virus infection has been increasingly appreciated since they were first discovered in mice more than 30 years ago (Herberman et al., 1975a,b). In this study, we report that placenta is a rich source of placenta-derived NK (pNK) cells that can be readily isolated from Combo units, followed by ex vivo expansion. Postpartum placentas and umbilical cords were procured under full-informed consent of donors with donor eligibility documentation, and were qualified using a series of tests, including serology, bacteriology, and HLA typing. The phenotype of mononuclear cells (MNCs) or enriched NK cells from Combo unit, or expanded cells from Day 7, 14, 21 cultures, was analyzed by multi-color flow cytometry.
Natural killer cell in vitro cytotoxicity was examined using NK cells as effector cells and various tumor cell lines as target cells.
Alternatively, NK cell in vitro cytotoxicity was examined by lactate dehydrogenase (LDH) release assay using CYTOTOX 96® colorimetric cytotoxicity assay kit (Promega). Human placenta-derived stem cells was harvested from three placentas separately and analyzed for cell surface markers by flow cytometry and compared to the donor-matched UCB.
Based on these similar phenotypic and functional characteristics and in order to increase the starting cell number, HPDSC and donor-matched UCB units were combined into one Combo unit, to be used as the starting material for further cell expansion. To qualify pNK as a reliable feed stock for this study and for future clinical production, a series of NK cell isolation experiments were performed to evaluate the consistency of recovery of pNK cells from the cryopreserved Combo units.
To compare pNK cells to PB NK cells, pNK cells from 16 Combo units and NK cells from 13 units of buffy coat obtained from PB were subjected to an extensive immunophenotypic characterization.
In attempts to compare gene expression profiles in pNK cells to PB NK cells, we discovered that individual donor variations in gene expression profiles were too large to evaluate differences between the placenta and PB NK sources. Researchers find that potent antibodies can be used to generate a specific type of cell that can be used to kill cells infected with HIV-1.
A type of immunotherapy that has shown promising results against cancer could also be used against HIV, the virus that causes AIDS. In a study published July 11 in the peer-reviewed Journal of Virology, researchers from the UCLA AIDS Institute and Center for AIDS Research found that recently discovered potent antibodies can be used to generate a specific type of cell called chimeric antigen receptors, or CARs, that can be used to kill cells infected with HIV-1.
CARs are artificially created immune T cells that have been engineered to produce receptors on their surface that are designed to target and kill specific cells containing viruses or tumor proteins.
Although the human body’s immune system does initially respond to and attack HIV, the sheer onslaught of the virus — its ability to hide in different T cells and to rapidly replicate — eventually wears out and destroys the immune system, leaving the body vulnerable to a host of infections and diseases. While the receptors approach has been in use for almost 10 years to fight cancer, this is the first attempt to use the technique to treat HIV since 15 years ago, when experiments proved unsuccessful. Here the researchers used seven recently discovered “broadly neutralizing antibodies” that have the ability to bind multiple strains of invading viruses, unlike earlier isolated antibodies that tend to bind few strains. Yang notes that “what works in a test tube doesn’t necessarily work in a person,” so the next step is to find strategies to put these receptors into humans. Tissue architecture is preserved for days and necrotic debris is ultimately removed by infiltrating leukocytes.
The ratio of T helper 1 (TH1)-cell cytokines to TH2-cell cytokines is increased after SIT, and functional regulatory T (TReg) cells are induced. The first defined differentiation stage has been termed the immature or intermediate DC stage.
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The FDA-approval of the CTLA-4 blocking antibody, ipilimumab (Bristol-Myers Squibb), and the PD-1 blocking antibody, pembrolizumab (Merck) in the treatment of advanced melanoma appear to represent the proverbial tip of the iceberg. Two phase 3 studies have demonstrated that the human CTLA-4 blocking antibody, ipilimumab, offers a benefit in overall survival for patients with advanced melanoma, leading to the FDA-approval of ipilimumab in March 2011 (Table 1) (8, 9). Selected clinical trials of CTLA-4 and PD-1 pathway blocking antibodies in advanced melanoma. Building upon the concept of PD-1 as a negative regulator of T cell function, subsequent studies demonstrated the potential for the PD-1 pathway to impact anti-tumor immune responses in a variety of mouse models of transplantable tumors. Furthermore, two early studies in mouse models of transplantable syngeneic tumors created further enthusiasm for this combination.
The inclusion of patients with stable disease for at least 24 weeks along with responders, defined as aggregate clinical activity rate, was 65% (50–83%) across all dose levels.
As of reporting for ASCO 2014, responses were ongoing for the majority of responding patient and the median duration of response across all combination cohorts had not been reached. While this was not a study requirement, the majority of patients enrolled in cohorts 6 and 7 had progressive disease after ipilimumab treatment, as assessed by their treating physician. These toxicities have been referred to as immune related adverse events (irAEs) and may affect any number of organ systems including the gastrointestinal tract (colitis, diarrhea), the lung (pneumonitis), the endocrine system (hypophysitis, thyroiditis), the liver (hepatitis), the skin (rash, pruritus), and the eye (uveitis) among others.
First, the observed toxicities all fall within the spectrum of irAEs already described for CTLA-4 or PD-1 pathway blocking agents; no distinctly new toxicities were described in this study.
For PD-1 and PD-L1 blocking antibodies, expression of PD-L1 in the tumor microenvironment has been intensely studies as a potential biomarker.
The true measure of the relative benefit, and toxicity, of this combination approach will be best established in larger, randomized studies. Hammers at the ASCO meeting in June of 2014 reflect two selected cohorts of a larger study, CA209-016 (NCT01472081) where nivolumab was tested in combination with TKI’s or ipilimumab for the treatment of metastatic RCC. Very consistent with the experience in melanoma, in patients treated with the combination of ipilimumab and nivolumab, PD-L1 status appears unrelated to response rate.

Antonio at the ASCO meeting in June of 2014 reflected two selected cohorts of a larger study, CA209-012 (NCT01454102) where nivolumab combinations were tested for the treatment of squamous or non-squamous advanced NSCLC. Evidence suggests that immunotherapy is most beneficial alone when employed early in the disease process or in combination with standard therapies (eg, radiation) later in the disease process.
The abscopal effect, also called the “distant bystander” effect, is a paradoxical effect of radiation on cellular systems whereby local radiation may have an antitumor effect on tumors distant from the site of radiation.[1] Indeed radiation’s ability to enhance distinct immune responses by inducing a “danger” signal that excites and activates the immune system has recently come under investigation. Although local control of the primary tumor can usually prevent development of subsequent systemic metastases, tumor radiation fails to control preexisting systemic disease, which may be present only as micrometastatic (and therefore undetectable) deposits.
As knowledge of the synergistic effects of radiation and immunotherapy increases, the translational use of this strategy for a variety of carcinomas will become more feasible. Tumor cells may not express the antigen transporter gene product TAP-2 and class I major histocompatibility complex (MHC) molecules,[3] and they lack T-cell costimulatory molecules such as B7-1 (CD80).
This chemokine switching acted as a homing receptor for activated DCs and facilitated the DC migration to draining lymph nodes.
Radiation-treated tumor cells would thus serve as an in situ autologous tumor vaccine,[13] inducing a strong tumor-specific immune response that could eradicate residual tumor cells in primary tumors and distant micrometastases (Figure 1). ICAM-1 and other cell adhesion molecules enhance T cells’ ability to kill target cells by improving cell-to-cell adhesion [14,15]. At each of these stages, unique proteins are expressed and upregulated in response to ionizing radiation, resulting in novel peptide presentation (Figure 2).[16] These novel peptides could cause activation of resting T cells specific for these epitopes, leading to an antitumor immune response. Garnett et al[17] examined 23 human carcinoma cell lines (12 colon, 7 lung, and 4 prostate) for their response to nonlytic doses of radiation (10 or 20 Gy).
These upregulated gene products may further enhance the tumor cells’ susceptibility to T cell–mediated immune attack or serve as additional targets for immunotherapy.
Improved understanding of the intertwined mechanisms involved in the augmentation of antitumor immunity by the addition of immunotherapy and radiation can further optimize this combination. These responses can occur at the initiation of T cell responses in lymph nodes (where the major APCs are dendritic cells) or in peripheral tissues or tumours (where effector responses are regulated). NK cells have also been shown to enhance transplant engraftment during allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Clinical studies exploring the biological activities of NK cells in the treatment of malignant disease and during allogeneic hematopoietic stem cell transplantation (HSCT) have provided promising results. Celgene Cellular Therapeutics (CCT, a division of Celgene Corporation) is developing human placenta-derived stem cells (HPDSC) as an adjunct to UCB cells for allogeneic use in first-degree or second-degree blood relatives for augmentation of the stem cell graft in hematopoietic reconstitution. We evaluated the proliferation, immunophenotype, miRNA expression, and activation of these expanded cells, as well as their cytolytic activities in vitro. HPDSC isolation and recovery was achieved by cannulation of the umbilical vessels (two arteries and one vein) under sterile conditions with polyethylene catheters connected to a flow-controlled fluid circuit allowing perfusion of the placenta.
In some NK cell expansion studies, peripheral blood mononuclear cells (PBMCs) obtained from buffy coat (Blood Center, NJ, USA) were prepared as an alternate source of NK cells.
The cells were harvested, fixed, and stained with anti-BrdU and 7-aminoactinomycin-D (7-AAD) following the protocol provided by the manufacturer.
The concentration and purity of the recovered small RNA was determined by measuring its absorbance at 260 and 280 nm. Genes that were predicted by five or more databases were considered as high confidence targets.
Chimeric receptors are the focus of ongoing research into how gene immunotherapy can be used to fight cancer. Researchers have been looking for ways to strengthen the immune system against HIV, and it now appears CARs could be a weapon in that fight.
The new research differs because it takes advantage of new antibodies that have been discovered in the past few years.
These antibodies were re-engineered as artificial CAR-T cell receptors to have activity against broad strains of HIV. Chu studied biological sciences at Brown University, Providence, Rhode Island, USA, and is a medical student in her final year at the Warren Alpert Medical School of Brown University. PAMPs include sugars, proteins, lipids and nucleic acids that are all recognized by the innate immune system. TReg cells express the transcription regulator forkhead box protein P3 (FOXP3), the lack of which predisposes to autoimmune diseases. The production of interleukin-10 (IL-10) by monocytes, macrophages, B cells and T cells is increased. Intermediate DCs differentiate from bone-marrow-derived progenitors in response to certain cytokines, of which granulocyte–macrophage colony-stimulating factor (GM-CSF) seems to be the most important. Now that safety and clinical activity has been demonstrated in the monotherapy setting, the field is moving in the direction of testing novel combinations. Accumulating clinical evidence points toward a promising role for checkpoint blocking antibodies in a rapidly expanding spectrum of additional solid tumors including non-small cell lung cancer, renal cell cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer. These studies supported the clinical development of agents that interrupt the PD-1 pathway via blockade of PD-1 itself, or one of its ligands, PD-L1.
The first study, presented by Korman and colleagues, demonstrated that the combination of PD-1 and CTLA-4 blockade had synergistic anti-tumor activity in a mouse model of colon adenocarcinoma, MC38 (28).
While cross-study comparisons are inherently limited, previously reported response rates for ipilimumab monotherapy and nivolumab monotherapy were 11 and 31%, respectively (8, 11, 32). The ORR in these two sequenced combination cohorts was 31% with all of these responses showing an 80% or greater reduction in disease burden.
In rare cases, toxicities may be severe and potentially life threatening (colitis, pneumonitis); however, in most cases, irAEs are reversible when managed according to standard algorithms that make use of immunosuppressive medications such as steroids. Second, the frequency of irAEs and the number of patients with multiple irAEs was notably higher than previously described for either monotherapy. In a small study (n = 9) from a single dose phase 1 study of nivolumab, Brahmer et al.
These studies are better positioned to address the outstanding questions of the relative benefits of concomitant vs. This stands in contrast to the experience with PD-L1 status in patients treated with PD-1 blockade alone. Three deaths that were due to drug-related toxicities were reported including 1 case each of respiratory failure following grade 3 colitis, pulmonary hemorrhage, and toxic epidermal necrolysis in a patient with a history of colitis. Additional approaches to testing combined CTLA-4 and PD-1 pathway blockade, including the combination of tremelimumab and MEDI4736 are also underway. Combining radiation therapy with immunotherapy allows one to exploit two broad areas: (1) radiation-induced tumor-cell death as a potential source of tumor antigens for immunotherapy, and (2) postirradiation tumor-cell modulation that allows more efficient immune-cell access and increased sensitivity to T-cell killing. However, it is often the case that not all tumor cells in a given mass receive a lethal dose of radiation due to dose constraints mandated by the need to limit damage to normal tissue. Irradiation can induce recognition and phagocytosis signals for dendritic cells (DCs), such as membrane-bound calreticulin, as well as release “danger” signals for DC activation,[2] such as various heat shock proteins (HSP) and high-mobility group protein B1 (HMGB1). These antigen-presenting cells then travel to regional lymph nodes where they present antigen to T cells, initiating or potentiating an antitumor immune response.
Studies have demonstrated that nonlethal doses of radiation induce a two-phase, dose-dependent increase in MHC class I presentation in human tumor cells.[16]. They examined changes in surface expression of Fas and other molecules involved in T cell–mediated immune attack, such as the adhesion molecule ICAM-1, TAAs such as carcinoembryonic antigen (CEA) and mucin-1 (MUC-1), and MHC class I. Taken together, these results suggest that nonlethal doses of radiation render human tumor cells more amenable to immune system recognition and attack.
In general, T cells do not respond to these ligand–receptor interactions unless they first recognize their cognate antigen through the TCR. The limited ex vivo expansion potential of NK cells from peripheral blood (PB) or umbilical cord blood (UCB) has however restricted their therapeutic potential.
Transplant studies have suggested alloreactive NK cells could mediate potent anti-leukemia effects without causing graft versus host disease (GVHD). Previous studies have highlighted the potential to selectively isolate and expand NK cells from UCB for adoptive cell transfer treatment of tumors (Xing et al., 2010).
We have established a standardized procedure to perfuse donated full-term placentas with normal saline to recover HPDSC. Our results demonstrate that pNK cells can be generated in clinically relevant quantities and may be developed as a highly cytotoxic cellular product that can be used to treat a wide range of cancers.
A total of 750 ml of perfusion solution (0.9% NaCl injection solution USP Grade) (VWR) was collected from each placenta. The cell cycle data was collected via FACSCalibur (BD Biosciences), and analysis was accomplished with FlowJo (Tree Star, Inc.). All analyses were performed using FACSCanto I (BD Biosciences) and FlowJo analysis software. After incubation, 50 μl supernatant was transferred to the enzymatic assay plate for detection of LDH activity as instructed by the manufacturer. Such targeted genes were then examined in pathway analysis (Ingenuity Systems) in order to determine the associated signaling pathways and cellular functions. In lab tests, the researchers found that all seven had varying degrees of ability to direct killer T cells to proliferate, kill and suppress viral replication in response to HIV-infected cells.
Her past research has focused on molecular and biochemical targets in oncology, including soluble receptors that are involved in tumour angiogenesis, pathways of ovarian cancer chemoresistance and motifs near the origin of replication that may underlie gene amplification. While single agent CTLA-4 or PD-1 pathway blockade has demonstrated clear anti-tumor activity across multiple tumor types, responding patients are still in the minority, underscoring the importance of improving upon present options. In a subsequent article by Curran et al., the authors confirmed the potent anti-tumor activity of this combination when used with a cellular vaccine (Gvax or Fvax) in the B16 murine model of melanoma (29).
One notable feature of the responses seen for patients treated with the combination was the relatively high rate of complete responses or near complete responses; 31% of the patients treated with the concomitant combination had a reduction in disease burden of 80% or greater. In aggregate, across all cohorts, the 1-year and 2-year survival was 85 and 79%, respectively. Clearly, some of the patients who did not have a response to ipilimumab monotherapy were able to respond to subsequent nivolumab treatment, a finding supported by a second independent study sequencing nivolumab after ipilimumab (33). Thus, pre-treatment PD-L1 tumor expression seems to have little predictive value in the setting of combination treatment, a finding that appears to be best explained by the relatively high rate of response to the combination seen in patients with PD-L1 negative tumors.
Similar to the melanoma experience, asymptomatic laboratory abnormalities such as elevations in AST, ALT, amylase, and lipase comprised the largest portion of grade 3–4 events.
As reported previous in both melanoma and RCC, PD-L1 status appeared to have no clear predictive value in patients with NSCLC treated with the combination of ipilimumab and nivolumab. As new agents become available, including checkpoint blocking antibodies against LAG-3, Tim-3, among other targets, new opportunities for combinations will abound. As monotherapies, both immunotherapy and radiation may be insufficient to eliminate tumor masses.
These tumor-specific T cells could arise endogenously or be induced from active vaccination strategies. Nevertheless, even sublethal doses of radiation can generate potent immmune responses by altering tumor cells in a variety of ways. Activated tumor-specific T cells can then traffic to areas of tumor to participate in immune-mediated tumor killing.
Radiation upregulated at least one of these surface molecules in 21 of 23 (91%) cell lines studied. Many of the ligands bind to multiple receptors, some of which deliver co-stimulatory signals and others deliver inhibitory signals. Here we define methods to efficiently generate NK cells from donor-matched, full-term human placenta perfusate (termed Human Placenta-Derived Stem Cell, HPDSC) and UCB.

HPDSC were subsequently processed to remove red blood cells, non-viable cells and tissue debris followed by cryopreservation. UCB was obtained by cannulation of the umbilical vein and collected into a bag containing citrate-phosphate-dextrose (Fenwal). Human miRNA Arrays (Applied Biosystems) were used for gene expression profiling and miRNA profiling. The two-sample t-test was used to determine if population means were equal in HPDSC and UCB. Otto Yang, professor of medicine in the division of infectious diseases at the David Geffen School of Medicine at UCLA and the study’s corresponding author. Intermediate DCs that develop and reside in peripheral tissues are specialized for antigen uptake and processing. Furthermore, in some tumors types, such as prostate cancer, single agents have a low level of activity that may be improved upon with combination approaches. At least two PD-1 blocking antibodies, pembrolizumab and nivolumab (Bristol-Myers Squibb) have demonstrated clinical activity in melanoma (Table 1), as well as several additional solid tumors including non-small cell lung cancer, renal cell cancer, ovarian cancer, and head and neck cancers (11–21). Additionally, they found that the activity of this triple combination was associated with an increase in effector T cells in the tumor microenvironment and a relative reduction in the frequency of regulatory T cells.
Additionally, two cohorts (6 and 7) allowed patients who had previously received commercial ipilimumab to receive nivolumab monotherapy as part of the study.
Based upon this initial activity, the study was expanded and an additional 41 patients treated with the concomitant combination of ipilimumab and nivolumab (cohort 8) were reported upon at ASCO in 2014. One interesting observation was generated in a retrospective analysis of residual plasma levels of ipilimumab. At this dose level, six patients were treated and three of these patients had grade 3 or 4 elevations in lipase that persisted for at least 3 weeks or longer.
In the initial report of cohorts 1–3 and 2A, no treatment related deaths were observed, but in the expanded study including cohort 8, 1 treatment related death (multi-organ failure related to colitis) was seen among the 94 patients treated.
Of course, testing for PD-L1 expression in a pre-treatment biopsy sample provides only a single static evaluation of PD-L1 expression and fails to capture dynamic changes in the PD-L1 expression that may accompany these treatments.
A randomized two-arm phase 2 study comparing the combination to ipilimumab monotherapy (NCT01927419) and a randomized three-arm phase 3 study comparing the combination to either nivolumab monotherapy or ipilimumab monotherapy (NCT01844505) have completed accrual and results are awaited. The primary endpoint of the study was safety and the secondary endpoints were ORR, duration of response, and progression free survival.
An important limitation in this comparison is that all patients in the phase 2 study were previously treated with 1–3 prior therapies including at least 1 antiangiogenic agent.
The primary endpoint of the study was safety and tolerability and the secondary endpoints were ORR and progression free survival at 24 weeks. However, following immunization with a cancer vaccine, the destruction of even a small percentage of tumor cells by radiation could result in crosspriming and presentation of tumor antigens to the immune system, thereby potentiating antitumor responses. Many of these peptides are generated by the proteasome from newly synthesized but rapidly degraded proteins (RDPs).
However, little information is available on the role of NK cells from placenta for cellular immunotherapy. Both UCB and perfusate were then processed by red blood cell depletion using Hetastarch, followed by volume reduction. In addition, SIT decreases the number of mast cells and the ability of mast cells to release mediators. Intermediate DCs express significant amounts of MHC class II, which is located predominantly in specialized antigen-processing vesicular compartments. Combined checkpoint blockade, to date explored with CTLA-4 and PD-1 pathway blocking agents, represents a first step in this new direction.
Pembrolizumab was approved by the FDA for previously treated advanced melanoma in September 2014.
In cohort 8, the ORR was 43 with 31% of patients showing a reduction in disease burden of 80% or greater.
Numerous subsequent studies have evaluated the potential for PD-L1 expression in the tumor microenvironment to predict response to PD-1 or PD-L1 blocking agents.
Additional studies looking at pharmacodynamic changes in the peripheral blood after treatment with ipilimumab and nivolumab demonstrated robust changes in immune activation markers such as ki67 and ICOS as well as upregulation of checkpoint molecules PD-1 and CTLA-4 (36). In contrast to the previously report study in melanoma, tumor response was assessed by RECIST v 1.1 criteria and the first tumor assessment was performed at 6 weeks.
No cases of grade 3–4 pneumonitis were observed in this study at the time of reporting. Learning how to exploit radiation-induced changes to tumor-cell antigens, and how to induce effective immune responses to these cumulatively immunogenic stimuli, is an exciting frontier in cancer therapy research.
Within 4 hours after exposure, the protein degradation triggered by radiation damage leads to an increased peptide pool (Figures 2 and 3). One important family of membrane-bound ligands that bind both co-stimulatory and inhibitory receptors is the B7 family.
However, a number of technical challenges have hampered the widespread application of NK cells in immunotherapy; these include a limited ability to generate large numbers of effector cells, difficulty in maintaining high tumoricidal activity during ex vivo expansion and in vivo therapy, and a limited understanding of NK-specific tumor targeting profiles. The resulting cell populations were cryopreserved in a solution containing 5% human albumin and 10% DMSO with a controlled rate freezer prior to final storage in the gas phase of a liquid nitrogen tank. To initiate NK cell expansion, the feeder cells and NK cell suspension was transferred into a gas permeable culture bag (American Fluoroseal) and was cultured in an incubator at 37°C in 5% CO2. After NK expansion for 21 days separately, HPDSC NK, and UCB NK cells showed comparable cytotoxicity against K562 cells at various E:T ratios, indicating functional similarity between HPDSC and UCB NK cells after expansion (Figure 1B).
Dupuy is the Director of Tumour Ablation at Rhode Island Hospital, USA, and a professor of diagnostic imaging at The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA. The maturation or activation of DCs occurs in response to a broad array of signals, which can generally be divided into two categories — pathogen-associated molecular pattern molecules (PAMPs) or endogenously produced signals of the tumour-necrosis factor (TNF) family.
Herein, we shall review the most up to date clinical data on these combinations, discussing both the promising clinical activity and the increased burden of toxicity seen in such combinations. Updated data on the long-term survival for the initial treatment cohorts as well as response rates and safety in an expanded number of patients treated on study (cohort 8) were reported at ASCO in 2014 (31). Collectively, the data seen in studies of nivolumab, pembrolizumab, MEDI4736, and MPDL3280a confirm that PD-L1 expression is a generally favorable feature associated with a higher rate of response to PD-1 pathway blockade [reviewed in Ref. In this small sample size, these pharmacodynamics changes did not correlate with clinical outcomes, but additional studies are ongoing exploring changes in peripheral blood and tumor markers in this setting.
The treatment schema was comparable to the schedule utilized in cohort 8 of the melanoma study; the combination was given every 3 weeks for up to for doses (so called induction) followed by nivolumab monotherapy administered every 2 weeks, or a maintenance phase. It is unclear what impact, if any, prior therapies may have had on the clinical activity or toxicity seen in the nivolumab plus ipilimumab combination. This review examines mechanisms by which many forms of radiation therapy can induce or augment antitumor immune responses as well as preclinical systems demonstrating that immunotherapy can be effectively combined with radiation therapy. All of the B7 family members and their known ligands belong to the immunoglobulin superfamily.
Therefore, there is a need to overcome these challenges and enable a NK cell-based anti-tumor strategy in the clinic. We hypothesize that HPDSC combined with the donor-matched UCB could represent an effective new source of NK cells that holds potential for further immunotherapeutic development. After culturing for 5–7 days, expanded cell populations were fed with Maintenance Medium for up to 21 days. The rationale for using the aforementioned criteria was to confirm that a miRNA is abundant in at least one donor sample, in comparison to the endogenous control.
He is a pioneer in the use of image-guided ablation and has helped to broaden the clinical applications of ablative techniques to successfully combat cancer of the kidney, liver, lung, head and neck, adrenal gland and skeleton. These two types of signal activate DC maturation through Toll-like receptors (TLRs) or TNF receptor (TNFR) family members, respectively. All of the patients treated in cohorts 1–3 and 2A were scheduled to receive concomitant doses ipilimumab and nivolumab every 3 weeks for a total of 4 doses and eligible patients who continued on treatment received the combination of both drugs every 3 months thereafter for up to 2 years. Finally, we review current clinical trials where standard-of-care radiation therapy is being combined with immunotherapy. Many of the receptors for more recently identified B7 family members have not yet been identified.
In addition to cell surface markers, different miRNA expression profiles have been associated with NK cell development, maturation, and function (Bezman et al., 2010). Donor samples without detectable levels of a miRNA were numerically ignored when averaging the Ct values. He has pioneered other, newer technologies, such as percutaneous microwave ablation, cryoablation and combination therapies using radiofrequency ablation with external radiation or brachytherapy, and he has been the Principal Investigator of two US National Cancer Institute (NCI)-funded multicentre trials. DC maturation starts with the expression of homing and chemokine receptors (such as CC-chemokine receptor 7 (CCR7)) that mediate traffic out of the tissue space and into draining lymph nodes through afferent lymphatics. Nevertheless, many of the patients who discontinued treatment had ongoing, durable responses that extended beyond ongoing treatment.
However, another clear message also emerges from this data; some patients who test negative for PD-L1 by the assays presently in use do respond to PD-1 blocking agents, albeit at a lower rate than their PD-L1 positive counterparts. Tumour necrosis factor (TNF) family members that bind to cognate TNF receptor family molecules represent a second family of regulatory ligand–receptor pairs. With further development, pNK may represent a novel and effective cellular immunotherapy for patients with high clinical needs and few other therapeutic options. A negative ΔCtmean along with two standard deviations from the control gene ensures that the particular gene is relatively abundant. He has received national awards for research and teaching from the American College of Radiology Imaging Network, the American College of Chest Physicians and the Radiological Society of North America (RSNA), where he served as the Chair of the Interventional Oncology Symposium that features at the Annual Meeting of the RSNA.
As they arrive in the paracortical regions of the draining lymph nodes, DCs upregulate their expression of co-stimulatory molecules, such as CD80 (B7-1) and CD86 (B7-2), and peptide-loaded MHC class II molecules transport from the intravesicular processing compartment to the cell surface. Several limitations to these studies remain to be resolved and explored including a lack of cross-study assay validation. These receptors predominantly deliver co-stimulatory signals when engaged by their cognate ligands. Additionally, all of the standard deviations of the reference genes were less than 0.25, which confirms the quality of the control. Mature DCs in the lymph node also secrete chemokines, such as thymus and activation-regulated chemokine (TARC; CC-chemokine17), which attract naive T cells. However, given the present status of the development of this biomarker, the lack of negative predictive value for this assay precludes patient selection at this time. Another major category of signals that regulate the activation of T cells comes from soluble cytokines in the microenviron-ment. He has authored more than 160 publications and given over 130 invited lectures in the field of radiology and image-guided ablation, both nationally and internationally.Contact Damian E. As described in the text, each of these DC maturation and activation steps is potentially amenable to regulation by engineered immunotherapy approaches.
In other cases, activated T cells upregulate ligands, such as CD40L, that engage cognate receptors on APCs.

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