Integrative Analysis of Programmed Death-Ligand 1 DNA, mRNA, and Protein Status and their Clinicopathological Correlation in Diffuse Large B-cell Lymphoma.

Histopathology. 2018 Oct 4.

2018 Oct 04

Sun C, Jia Y, Wang W, Bi R, Wu L, Bai Q, Zhou X.
PMID: 30286249 | DOI: 10.1111/his.13765

Abstract AIMS: The Protein expression of Programmed Death-Ligand 1 (PD-L1) has been recognized a poor prognostic biomarker in diffuse large B-cell lymphoma (DLBCL). We aim to detect PD-L1 DNA and mRNA status, and explore whether they contribute to protein expression and their clinicopathological correlation in DLBCL. METHODS AND RESULTS: In the study, we detected PD-L1 status in three different levels by Fluorescence in situ hybridization, RNA in situ hybridization and immunohistochemistry in 287 DLBCL samples with follow-ups, respectively. Their correlation and clinical pathological relevance was further analyzed. Our results showed that 1.7% (3/175) patients had PD-L1 amplification, 19.9% (57/287) PD-L1 mRNA high expression and 11.8% (34/287) high protein expression. Both mRNA and protein high expression of PD-L1 was significantly elevated in non-GCB than that in GCB DLBCL (P<0.05). In addition, the patients with PD-L1 mRNA or protein high expression but not DNA amplification have significantly poorer overall survival (OS) than that with PD-L1 low expression (P<0.05). Furthermore, we found that PD-L1 mRNA and protein expression are highly correlated (P=0.012), which was observed in all three samples with PD-L1 DNA amplification. CONCLUSIONS: PD-L1 DNA amplification is a rare event, PD-L1 mRNA mainly contribute to the protein high expression, and the latter two will serve as important biomarkers for predicting prognosis and selecting patients for immunotherapy in DLBCL.

TGF-? inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors

JCI insight

2020 Feb 27

Tang N, Cheng C, Zhang X, Qiao M, Li N, Mu W, Wei XF, Han W, Wang H
PMID: 31999649 | DOI: 10.1172/jci.insight.133977 Free full text

In recent years, chimeric antigen receptor-modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here, we demonstrated that knocking out the endogenous TGF-? receptor II (TGFBR2) in CAR T cells with CRISPR/Cas9 technology could reduce the induced Treg conversion and prevent the exhaustion of CAR T ce lls. Meanwhile, TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line-derived xenograft and patient-derived xenograft solid tumor models, whether administered locally or systemically. In addition, the TGFBR2-edited CAR T cells could eliminate contralaterally reinoculated xenografts in mice effectively, with an increased proportion of memory subsets within circulating CAR T cells of central memory and effector memory subsets. In conclusion, we greatly improved the in vitro and in vivo function of CAR T cells in TGF-?-rich tumor environments by knocking out endogenous TGFBR2 and propose a potentially new method to improve the efficacy of CAR T cell therapy for treating solid tumors

Programmed death-ligand-1 expression in advanced gastric cancer detected with RNA in situ hybridization and its clinical significance.

Oncotarget.

2016 May 15

Yuan J, Zhang J, Zhu Y, Li N, Tian T, Li Y, Li Y, Li Z, Lai Y, Gao J, Shen L.
PMID: 27191996 | DOI: 10.18632/oncotarget.9381

PD-L1 expression may be a predictive marker for anti-PD-1 therapeutic efficacy. No standard detection method of PD-L1 expression was available for advanced gastric cancer (AGC), which would be investigated in this study using RNA in situ hybridization and immunohistochemistry. Patients (N = 165) with AGC treated at Peking University Cancer Hospital from October 2008 to February 2013 were retrospectively studied. Tissue samples prior to chemotherapy were assessed for PD-L1 expression using RNA in situ hybridization (an RNAscope assay) and immunohistochemistry (IHC). The correlations of PD-L1 expression to patient characteristics and clinical outcomes were statistically analyzed. PD-L1 mRNA signals were located in tumor compartments or the mesenchyme in a brown dotted or clustered pattern, and PD-L1 mRNA expression in gastric cancer was heterogeneous. PD-L1-positive expressions were observed in 33.9% (56/165) and 35.1% (46/131) patients in mRNA level and protein level, respectively. A positive relationship was found between PD-L1 mRNA and PD-L1 protein, and compared to IHC, RNAscope assay could provide an intuitional and quantitative data with potential clinical application. No statistically significant differences occurred between PD-L1 expression and clinical response to chemotherapy, or survival. However, we found that PD-L1 expression was higher in intestinal type than in diffuse type. These findings suggested that the RNAscope assay may be a promising method for patient assessment in gastric cancer clinical trials, which would be illustrated in further study.

HDAC inhibition potentiates immunotherapy in triple negative breast cancer

Oncotarget.

2017 Dec 12

Terranova-Barberio M, Thomas S, Ali N, Pawlowska N, Park J, Krings G, Rosenblum MD, Budillon A, Munster PN.
PMID: - | DOI: 10.18632/oncotarget.23169

ABSTRACT

Triple-negative breast cancer (TNBC) represents a more aggressive and difficult subtype of breast cancer where responses to chemotherapy occur, but toxicity is significant and resistance often follows. Immunotherapy has shown promising results in various types of cancer, including breast cancer. Here, we investigated a new combination strategy where histone deacetylase inhibitors (HDACi) are applied with immune checkpoint inhibitors to improve immunotherapy responses in TNBC.

Testing different epigenetic modifiers, we focused on the mechanisms underlying HDACi as priming modulators of immunotherapy. Tumor cells were co-cultured with human peripheral blood mononuclear cells (PBMCs) and flow cytometric immunophenotyping was performed to define the role of epigenetic priming in promoting tumor antigen presentation and immune cell activation. We found that HDACi up-regulate PD-L1 mRNA and protein expression in a time-dependent manner in TNBC cells, but not in hormone responsive cells. Focusing on TNBC, HDACi up-regulated PD-L1 and HLA-DR on tumor cells when co-cultured with PBMCs and down-regulated CD4+ Foxp3+ Treg in vitro. HDACi significantly enhanced the in vivo response to PD-1/CTLA-4 blockade in the triple-negative 4T1 breast cancer mouse model, the only currently available experimental system with functional resemblance to human TNBC. This resulted in a significant decrease in tumor growth and increased survival, associated with increased T cell tumor infiltration and a reduction in CD4+Foxp3+ T cells in the tumor microenvironment. Overall, our results suggest a novel role for HDAC inhibition in combination with immune checkpoint inhibitors and identify a promising therapeutic strategy, supporting its further clinical evaluation for TNBC treatment.

Preclinical proof of concept for VivoVec, a lentiviral-based platform for in vivo CAR T-cell engineering

Journal for immunotherapy of cancer

2023 Mar 01

Michels, KR;Sheih, A;Hernandez, SA;Brandes, AH;Parrilla, D;Irwin, B;Perez, AM;Ting, HA;Nicolai, CJ;Gervascio, T;Shin, S;Pankau, MD;Muhonen, M;Freeman, J;Gould, S;Getto, R;Larson, RP;Ryu, BY;Scharenberg, AM;Sullivan, AM;Green, S;
PMID: 36918221 | DOI: 10.1136/jitc-2022-006292

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformational outcomes in the treatment of B-cell malignancies, but their widespread use is hindered by technical and logistical challenges associated with ex vivo cell manufacturing. To overcome these challenges, we developed VivoVec, a lentiviral vector-based platform for in vivo engineering of T cells. UB-VV100, a VivoVec clinical candidate for the treatment of B-cell malignancies, displays an anti-CD3 single-chain variable fragment (scFv) on the surface and delivers a genetic payload that encodes a second-generation CD19-targeted CAR along with a rapamycin-activated cytokine receptor (RACR) system designed to overcome the need for lymphodepleting chemotherapy in supporting successful CAR T-cell expansion and persistence. In the presence of exogenous rapamycin, non-transduced immune cells are suppressed, while the RACR system in transduced cells converts rapamycin binding to an interleukin (IL)-2/IL-15 signal to promote proliferation.UB-VV100 was administered to peripheral blood mononuclear cells (PBMCs) from healthy donors and from patients with B-cell malignancy without additional stimulation. Cultures were assessed for CAR T-cell transduction and function. Biodistribution was evaluated in CD34-humanized mice and in canines. In vivo efficacy was evaluated against normal B cells in CD34-humanized mice and against systemic tumor xenografts in PBMC-humanized mice.In vitro, administration of UB-VV100 resulted in dose-dependent and anti-CD3 scFv-dependent T-cell activation and CAR T-cell transduction. The resulting CAR T cells exhibited selective expansion in rapamycin and antigen-dependent activity against malignant B-cell targets. In humanized mouse and canine studies, UB-VV100 demonstrated a favorable biodistribution profile, with transduction events limited to the immune compartment after intranodal or intraperitoneal administration. Administration of UB-VV100 to humanized mice engrafted with B-cell tumors resulted in CAR T-cell transduction, expansion, and elimination of systemic malignancy.These findings demonstrate that UB-VV100 generates functional CAR T cells in vivo, which could expand patient access to CAR T technology in both hematological and solid tumors without the need for ex vivo cell manufacturing.

PD-L1 expression in lung adenosquamous carcinomas compared with the more common variants of non-small cell lung cancer.

Sci Rep.

2017 Apr 07

Shi X, Wu S, Sun J, Liu Y, Zeng X, Liang Z.
PMID: 28387300 | DOI: 10.1038/srep46209

Lung adenosquamous cell carcinomas (ASCs) is a rare variant of NSCLC with a poorer prognosis and fewer treatment option than the more common variants. PD-L1 expression is reported to be the predictor of clinical response in trials of NSCLC. In our study, PD-L1 expression was evaluated via immunohistochemistry using a specific monoclonal antibody (SP263), and PD-L1 mRNA expression was evaluated via in situ hybridization. This study included 51 ASCs, 133 lung adenocarcinomas, and 83 lung squamous cell carcinomas (SCC). Similar results were obtained for PD-L1 expression measured at the mRNA and protein level (k coefficient, 0.851, P = 1.000). PD-L1 expression was significantly higher in the squamous versus glandular component of the 36 ASCs in which the components were analyzed separately. The PD-L1 expression rate was similar in the squamous cell component of ASCs and lung SCC (38.89% vs. 28.92%, P = 0.293), so does the adenocarcinoma component of ASCs and lung adenocarcinomas (11.11% vs 13.53%, P = 1.000). PD-L1 expression correlated significantly with lymphovascular invasion (P = 0.016), but not with EGFR, KRAS, and ALK mutations in lung ASCs. Anit-PD-L1 is a promising treatment option in lung ASC cases in which PD-L1 upregulated and EGFR mutations are present.

Nonclinical pharmacokinetics and biodistribution of VSV-GP using methods to decouple input drug disposition and viral replication

Molecular Therapy - Methods & Clinical Development

2022 Dec 01

Dambra, R;Matter, A;Graca, K;Akhand, S;Mehta, S;Bell-Cohn, A;Swenson, J;Abid, S;Xin, D;Lewis, C;Coyle, L;Wang, M;Bunosso, K;Maugiri, M;Ruiz, R;Cirillo, C;Fogal, B;Grimaldi, C;Vigil, A;Wood, C;Ashour, J;
| DOI: 10.1016/j.omtm.2022.12.013

Viral replication places oncolytic viruses (OVs) in a unique niche in the field of drug pharmacokinetics (PK) as their self-amplification obscures exposure-response relationships. Moreover, standard bioanalytical techniques are unable to distinguish the input from replicated drug products. Here, we combine two novel approaches to characterize PK and biodistribution (BD) after systemic administration of vesicular stomatitis virus pseudotyped with lymphocytic choriomeningitis virus glycoprotein (VSV-GP) in healthy mice. First: to decouple input drug PK/BD versus replication PK/BD, we developed and fully characterized a replication-incompetent tool virus that retained all other critical attributes of the drug. We used this approach to quantify replication in blood and tissues and to determine its impact on PK and BD. Second: to discriminate the genomic and antigenomic viral RNA strands contributing to replication dynamics in tissues, we developed an in situ hybridization method using strand-specific probes and assessed their spatiotemporal distribution in tissues. This latter approach demonstrated that distribution, transcription, and replication localized to tissue-resident macrophages, indicating their role in PK and BD. Ultimately, our study results in a refined PK/BD profile for a replicating OV, new proposed PK parameters, and deeper understanding of OV PK/BD using unique approaches that could be applied to other replicating vectors.

PD-1/PD-L1 Pathway: A Therapeutic Target in CD30+ Large Cell Lymphomas

Biomedicines

2022 Jul 04

Xie, W;Medeiros, LJ;Li, S;Tang, G;Fan, G;Xu, J;
PMID: 35884893 | DOI: 10.3390/biomedicines10071587

The programmed death-ligands, PD-L1 and PD-L2, reside on tumor cells and can bind with programmed death-1 protein (PD-1) on T-cells, resulting in tumor immune escape. PD-1 ligands are highly expressed in some CD30+ large cell lymphomas, including classic Hodgkin lymphoma (CHL), primary mediastinal large B-cell lymphoma (PMBL), Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL), and anaplastic large cell lymphoma (ALCL). The genetic alteration of the chromosome 9p24.1 locus, the location of PD-L1, PD-L2, and JAK2 are the main mechanisms leading to PD-L1 and PD-L2 overexpression and are frequently observed in these CD30+ large cell lymphomas. The JAK/STAT pathway is also commonly constitutively activated in these lymphomas, further contributing to the upregulated expression of PD-L1 and PD-L2. Other mechanisms underlying the overexpression of PD-L1 and PD-L2 in some cases include EBV infection and the activation of the mitogen-activated protein kinase (MAPK) pathway. These cellular and molecular mechanisms provide a scientific rationale for PD-1/PD-L1 blockade in treating patients with relapsed/refractory (R/R) disease and, possibly, in newly diagnosed patients. Given the high efficacy of PD-1 inhibitors in patients with R/R CHL and PMBL, these agents have become a standard treatment in these patient subgroups. Preliminary studies of PD-1 inhibitors in patients with R/R EBV+ DLBCL and R/R ALCL have also shown promising results. Future directions for these patients will likely include PD-1/PD-L1 blockade in combination with other therapeutic agents, such as brentuximab or traditional chemotherapy regimens.

Olfactory Receptor OR2H1 is an effective target for CAR T cells in human epithelial tumors

Molecular cancer therapeutics

2022 May 02

Martin, AL;Anadon, CM;Biswas, S;Mine, JA;Handley, KF;Payne, KK;Mandal, G;Chaurio, RA;Powers, JJ;Sprenger, KB;Rigolizzo, KE;Innamarato, P;Harro, CM;Mehta, S;Perez, BA;Wenham, RM;Conejo-Garcia, JR;
PMID: 35499393 | DOI: 10.1158/1535-7163.MCT-21-0872

Though chimeric antigen receptor (CAR) expressing T cells have proven success in hematologic malignancies, their effectiveness in solid tumors has been largely unsuccessful thus far. We found that some olfactory receptors are expressed in a variety of solid tumors of different histological subtypes, with a limited pattern of expression in normal tissues. Quantification of OR2H1 expression by RT-QPCR and western blot analysis of 17 normal tissues, 82 ovarian cancers of various histologies, 8 non-small cell lung cancers (NSCLC), and 17 breast cancers demonstrated widespread OR2H1 expression in solid epithelial tumors with expression in normal human tissues limited to the testis. CAR T cells recognizing the extracellular domain of the olfactory receptor OR2H1 were generated with a targeting motif identified through the screening of a phage display library and demonstrated OR2H1-specific cytotoxic killing in vitro and in vivo, using tumor cells with spontaneous expression of variable OR2H1 levels. Importantly, recombinant OR2H1 IgG generated with the VH/VL sequences of the CAR construct specifically detected OR2H1 protein signal in 60 human lung cancers, 40 ovarian carcinomas and 73 cholangiocarcinomas, at positivity rates comparable to mRNA expression and without OR2H1 staining in 58 normal tissues. CRISPR/Cas9-mediated ablation of OR2H1 confirmed targeting specificity of the CAR and the tumor-promoting role of OR2H1 in glucose metabolism. Therefore, T cells redirected against OR2H1-expressing tumor cells represent a promising therapy against a broad range of epithelial cancers, likely with an admissible toxicity profile.

Listeria delivers tetanus toxoid protein to pancreatic tumors and induces cancer cell death in mice

Science translational medicine

2022 Mar 23

Selvanesan, BC;Chandra, D;Quispe-Tintaya, W;Jahangir, A;Patel, A;Meena, K;Alves Da Silva, RA;Friedman, M;Gabor, L;Khouri, O;Libutti, SK;Yuan, Z;Li, J;Siddiqui, S;Beck, A;Tesfa, L;Koba, W;Chuy, J;McAuliffe, JC;Jafari, R;Entenberg, D;Wang, Y;Condeelis, J;DesMarais, V;Balachandran, V;Zhang, X;Lin, K;Gravekamp, C;
PMID: 35320003 | DOI: 10.1126/scitranslmed.abc1600

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease. Tumors are poorly immunogenic and immunosuppressive, preventing T cell activation in the tumor microenvironment. Here, we present a microbial-based immunotherapeutic treatment for selective delivery of an immunogenic tetanus toxoid protein (TT856-1313) into PDAC tumor cells by attenuated Listeria monocytogenes. This treatment reactivated preexisting TT-specific memory T cells to kill infected tumor cells in mice. Treatment of KrasG12D,p53R172H, Pdx1-Cre (KPC) mice with Listeria-TT resulted in TT accumulation inside tumor cells, attraction of TT-specific memory CD4 T cells to the tumor microenvironment, and production of perforin and granzyme B in tumors. Low doses of gemcitabine (GEM) increased immune effects of Listeria-TT, turning immunologically cold into hot tumors in mice. In vivo depletion of T cells from Listeria-TT + GEM-treated mice demonstrated a CD4 T cell-mediated reduction in tumor burden. CD4 T cells from TT-vaccinated mice were able to kill TT-expressing Panc-02 tumor cells in vitro. In addition, peritumoral lymph node-like structures were observed in close contact with pancreatic tumors in KPC mice treated with Listeria-TT or Listeria-TT + GEM. These structures displayed CD4 and CD8 T cells producing perforin and granzyme B. Whereas CD4 T cells efficiently infiltrated the KPC tumors, CD8 T cells did not. Listeria-TT + GEM treatment of KPC mice with advanced PDAC reduced tumor burden by 80% and metastases by 87% after treatment and increased survival by 40% compared to nontreated mice. These results suggest that Listeria-delivered recall antigens could be an alternative to neoantigen-mediated cancer immunotherapy.

Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small cell lung cancer patients.

Ann Oncol.

2017 Jun 08

Sanmamed MF, Perez-Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez-Ruiz ME, Oñate C, Perez G, Alfaro C, Martín-Algarra S, Andueza MP, Gurpide A, Morgado M, Wang J, Bacchiocchi A, Halaban R, Kluger H, Chen L, Sznol M, Melero I.
PMID: 28595336 | DOI: 10.1093/annonc/mdx190

Abstract

Background

Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small cell lung cancer (NSCLC) patients.

Patients and methods

Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab, were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics (ROC) curves.

Results

Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P < .001), and significantly increased upon progression (P = .004). In non-responders, IL-8 levels significantly increased between baseline and progression (P = .013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P < .001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P = .001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P < .001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P = .001) and NSCLC (P = .015) patients. Serum IL-8 levels also correctly reflected true response in 3 cancer patients presenting pseudoprogression.

Conclusions

Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.

PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer

Clin Cancer Res.

2017 Jun 15

Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, Lunceford J, Cheng J, Chow LQM, Seiwert TY, Handa M, Tomassini JE, McClanahan T.
PMID: 28619999 | DOI: 10.1158/1078-0432.CCR-16-1761

Abstract

Purpose: Tumor-associated PD-L1 expression is predictive of clinical response to PD-1-directed immunotherapy. However, PD-L1-negative patients may also respond to PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated.Experimental Design: PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay. In addition, relationships between clinical response and PD-L2 status were evaluated in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC) with recurrent or metastatic disease, treated with pembrolizumab.Results: PD-L2 expression was observed in all tumor types and present in stromal, tumor, and endothelial cells. The prevalence and distribution of PD-L2 correlated significantly with PD-L1 (P = 0.0012-<0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity significantly predicted clinical response to pembrolizumab on combined tumor, stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status. Longer median times for PFS and overall survival were observed for PD-L2-positive than PD-L2-negative patients.Conclusions: Clinical response to pembrolizumab in patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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