NK cells act as the body's first line of defense against cancer cells. They quickly recognize and kill tumor cells without prior exposure. Adoptive cell therapy (ACT) using NK cells shows promise against hematological cancers. Cytotoxic activity of these cells is restricted by inhibitory receptors that reduce NK cell-mediated cytotoxicity. Overcoming this inhibition would allow for a more potent antitumor response following ACT and potential application against solid tumors. We have developed a new class of stable, self-delivering RNAi compounds (INTASYL) that incorporate features of RNAi and antisense technology. INTASYL compounds demonstrate potent activity, stability, and are rapidly and efficiently taken up by cells. INTASYL PH-804 targeting the inhibitory receptor TIGIT enhances the cytotoxic activity of expanded human NK cells in vitro.
Methods
Primary human CD56+ NK cells were expanded using the ImmunoCult™ NK Cell Expansion Kit from StemCell Technologies. Following the 14-day expansion protocol, cells were collected, and the cell density was adjusted to 0.5 x 106 cells/mL in culture media containing IL-2. Cells were seeded directly into 24-well plates containing PH-804 ranging in final concentration from 1 μM to 5 μM. Taqman gene expression assays were used to determine expression levels of TIGIT following the RNA-to-Ct 1-step protocol. In addition, cells were stained using fluorescently labeled antibodies for flow cytometry. Cytotoxic capabilities of the PH-804 transfected NK cells against the K562 (Chronic Myelogenous Leukemia) cancer cell line were tested in a DELFIA cell cytotoxicity assay.
Results
Transfection with PH-804 results in consistent mRNA and protein silencing without negative impact on NK cell viability. For example, treatment with 5 μM PH-804 results in a 60% reduction in TIGIT mRNA. The reduction is seen at >7 days post-transfection and results in a 45% reduction in surface expression of TIGIT by flow cytometry. Silencing of TIGIT with PH-804 resulted in increased expression of markers of NK cell activation and increased cytotoxic capabilities of NK cells against K562 cancer cells in the DELFIA cell cytotoxicity assay.
Conclusions
Here, we demonstrate the potential of PH-804 to improve NK cell potency in ACT. By treating NK cells with INTASYL targeting the inhibitory receptor TIGIT ex vivo, during NK cell expansion, the anti-tumor response of these cells was enhanced potentially resulting in a more effective cell therapy for solid tumors and hematological malignancies.
We have identified a domain in the N terminus of huntingtin that binds to membranes. A three-dimensional homology model of the structure of the binding domain predicts helical HEAT repeats, which emanate a positive electrostatic potential, consistent with a charge-based mechanism for membrane association. An amphipathic helix capable of inserting into pure lipid bilayers may serve to anchor huntingtin to the membrane. In cells, N-terminal huntingtin fragments targeted to regions of plasma membrane enriched in phosphatidylinositol 4,5-bisphosphate, receptor bound-transferrin, and endogenous huntingtin. N-terminal huntingtin fragments with an expanded polyglutamine tract aberrantly localized to intracellular regions instead of plasma membrane. Our data support a new model in which huntingtin directly binds membranes through electrostatic interactions with acidic phospholipids.
Abstract The intestinal microbiome has become increasingly appreciated as a significant mediator of systemic antitumor immunity/response in both naïve and treatment contexts. In naïve contexts, an intact intestinal microbiome has been demonstrated to enhance tumorigenesis, and its composition to mediate primary tumor growth kinetics. In the context of cancer treatment, antibiotic depletion of the intestinal microbiota has been reported to inhibit the efficacy of cyclophosphamide and that of the immune checkpoint inhibitor αCTLA4. Compositional modulation of the intestinal microbiota has been found to be sufficient to enhance the antitumor efficacy of αPD-L1. Here, we assessed the relative importance of the intestinal microbiota in mediating αPD-L1 antitumor efficacy in a B16.F10.SIY murine model of melanoma, by performing parallel efficacy studies in C57BL/6 germ-free (Taconic) or specific pathogen free (Taconic or Jackson) mice. We observed that αPD-L1 treatment provided significant antitumor efficacy of in Taconic mice carrying an intact microbiome; however, this efficacy was abolished in germ-free Taconic mice. Furthermore, we observed that tumors of Jackson mice carrying an intact but compositionally different microbiome did not respond to αPD-L1 treatment. Phenotyping of local tumor and systemic immune responses, as well as characterization of the intestinal microbiome in responder vs nonresponder animals provided mechanistic insights. Taken together, these observations suggest that rational modulation of the microbiome may enhance response to immune checkpoint inhibition, and indicate that the gastrointestinal microbiome and its composition are critical for the antitumor efficacy of αPD-L1. Citation Format: Benjamin G. Cuiffo, Caitlin S. Parello, Chelsea Ritchie, Katie Pedrick, Alexandra Kury, Catarina Costa, Brett Van Dam, Jonathan Jung, Gregory D. Lyng, Stephen T. Sonis. The gastrointestinal microbiome and its composition are critical for antitumor efficacy of immune checkpoint inhibition by anti-PD-L1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2683. doi:10.1158/1538-7445.AM2017-2683
Abstract Background: Only 5% of investigational anti-cancer agents are ultimately clinically successful. This may be attributed in part to the historical preclinical use of human cell lines that poorly recapitulate tumor heterogeneity in imperfect xenograft models. To model critical influences of tissue environment on tumor behavior and therapeutic response, heterogeneous patient-derived xenografts (PDX) can be assayed following implantation at orthotopic sites in rodents. Challenges to this approach include inaccessibility of certain organs or inability to track residual or metastatic disease. To address these problems, we utilized pancreatic (PANx-005) or metastatic breast (HBCx-14) PDXs transduced with stable bioluminescent reporters in efficacy studies of standard of care (SOC) and experimental treatments in clinically recapitulative models. Methods: Freshly excised PDXs were transduced with lentiviral vectors stably expressing luciferase, and implanted orthotopically into NOD scid gamma (NSG) mice. For our primary pancreatic cancer model, the pancreas was surgically exposed, and ∼2.5 × 106 PANx-005-Luc cells were inoculated directly. Post-op, tumor growth was monitored in-life (Xenogen IVIS® Lumina Series III instrument (IVIS)). Mice were randomized into treatment groups when mean tumor radiance (TR) reached 3.0 × 106 photons/sec. Control animals received no treatment; SOC groups received either focused fractionated radiation (12 Gy as 3×4 Gy fractions, Q5D (SRT)) or gemcitabine (75 mg/kg, 2QWx4, i.p.), and the experimental group received (+)-JQ-1 BET bromodomain inhibitor (50 mg/kg, QD, i.p.). For the residual/metastatic breast cancer model, ∼1.5 × 106 HBCx-14-Luc were injected directly into the 4th inguinal mammary fat pad. Tumor growth and response were monitored throughout the study by IVIS. When individual TR reached 7.5 × 109 photons/sec, the primary tumor was resected and the animal enrolled into a treatment group to be treated for residual/metastatic disease. Control animals received no treatment; SOC groups received either SRT, capacetabine (540 mg/kg QDx5/ 1week rest, p.o.) or docetaxel (20 mg/kg, Q3Wx2, i.p.); while experimental animals received (+)-JQ-1 (50 mg/kg, QD, i.p.). Results: Tumor seeding approached 100% in both models. Growth kinetics resembled clinical indications, including rapid growth and lung metastases for the HBCx-14 tumors, and slower growth of PANCx-005 tumors. Efficacies of individual treatments recapitulated clinical responses: HBCx-14 tumors were high responders to capecitabine and (+)-JQ-1, and low-responders to docetaxel, while PANx-005 tumors displayed high response to (+)-JQ-1 and lower response to gemcitabine. Conclusions: The translational predictivity of preclinical cancer models is enhanced by the use of human PDXs that preserve tumor heterogeneity, are assayed at orthotopic sites, and are utilized in models that recapitulate clinical situations (e.g. treatment of residual disease vs primary tumor). The use of stable bioluminescent reporters in such assays greatly enhances precision in monitoring tumor growth and treatment response. Currently available preclinical oncology models are more recapitulative, precise and predictive than ever before, and appear poised to engender improved translational success. Citation Format: Benjamin G. Cuiffo, Olivier Deas, Gregory D. Lyng, Stephano Cairo, Enora Le Ven, Jean-Gabriel Judde, Stephen T. Sonis. Bioluminescent orthotopic PDX models of primary pancreatic cancer and residual/metastatic breast cancer predict efficacy of standard of care and experimental treatments. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A9.
Humanized immune system (HIS) mice - immunocompromised Nod.Cg-Prkdcscid Il2rgtm1Wjl/SzJ animals in which the immune system has been humanized by the engraftment of CD34+ hematopoietic stem cells (HSC), peripheral blood mononuclear cells (PBMC), or other human cells/tissues - represent an important tool in pre-clinical oncology research. Here we investigated several pre-conditioning regimens (Busulfan pre-treatment or total body irradiation (TBI)) to determine which would yield maximum human leukocyte engraftment and lineage diversity. Animals were pre-treated either one or two doses of Busulfan (25 mg/kg) or varying doses of TBI (1.75, 2.0, or 2.5 Gy). One to two days later, animals received an adoptive transfer of native hCD34+ HSCs. Engraftment was monitored by flow cytometry assessment of peripheral blood four weeks after adoptive-transfer, and every four weeks thereafter through experiment termination at Week 16. Upon termination, spleen and bone-marrow were assessed for various leukocyte populations by flow cytometry. Animals undergoing pre-conditioning displayed increased human CD45+ cell engraftment at all timepoints as compared to animals without pre-conditioning, with animals treated with two doses of Busulfan demonstrating the greatest human CD45+ engraftment at all timepoints and reaching statistical significance at endpoint (vs no pre-conditioning; p<0.05). Diversity of leukocyte cell types (B cells, T cells, NK cells, and other hCD45+) in the bone-marrow was similar across pre-treatment paradigms, however for some lineages, representation in the bone-marrow was significantly altered between pre-conditioning type. The absolute number of T or B cells were increased in TBI and Busulfan treated groups, respectively, whereas NK cells as a percentage of singlets were increased in TBI treated groups. The diversity of leukocyte cell types in the spleen was likewise similar across groups, with B cells dominating. These data provide important insights into the utility of various pre-conditioning regimens for the humanization of NSG mice for pre-clinical oncology research, and demonstrate that the optimum pre-conditioning regimens should be selected based on treatment target.Citation Format: Caitlin S. Parello, Benjamin G. Cuiffo, Alexandria Kury, Kasey Reardon, Brett Van Dam, Sallyann Vu, Catarina Costa, Veronica Ritchie, Gavin Gagnon, Timothy Bateson, Samantha Rogers, Gregory D. Lyng, Stephen T. Sonis. An assessment of pre-conditioning regimens for optimal hCD34+ hematopoietic stem cell humanization of NSGTMmice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 511.
Abstract Background: BRD4 is a member of the family of bromodomain and extra-terminal motif (BET) proteins that act as epigenetic readers and regulators of gene transcription. BRD4 has been shown to be significantly upregulated in cancer including melanoma, with preclinical data supporting BRD4 inhibition as a promising therapeutic target. However, clinical translation of BRD4 inhibitors (BRD4i) has remained elusive. Current small molecule inhibitors of BET proteins are not specific to BRD4 as demonstrated by their inhibition of other members of the BET protein family. Additionally, systemic approaches must overcome a narrow therapeutic window. The INTASYL™ platform is a self-delivering RNAi technology that imparts small molecule-like properties to interfering RNAs, providing efficient delivery to target cells without need for specialized formulations or drug delivery systems. PH-894 is an INTASYL compound that silences BRD4 mRNA. PH-894 has been shown to specifically silence BRD4 mRNA and provide robust direct and abscopal antitumor efficacy in vivo when administered intratumorally (IT). Therefore, IT PH-894 holds promise to realize the therapeutic potential of BRD4 inhibition by avoiding toxicities associated with systemic delivery of small molecule BET inhibitors. Here, we explored the impact of PH-894 mediated BRD4 inhibition on antigenicity of melanoma tumor cells. Specifically, expression of the melanoma tumor-associated antigen MART-1 was studied following PH-894 treatment. Methods: SK-MEL-5 melanoma cells were treated for 72 hours with PH-894 or a non-targeting control (NTC) INTASYL compound. After 72 hours (Day 3), PH-894 was washed out and cells were replated in media containing no INTAYSL compound for the duration of the experiment. Cells were collected for analysis of both BRD4 and MART-1 mRNA and protein from Day 3 through Day 7. Results: PH-894 provided robust silencing of BRD4 mRNA and protein in SK-MEL-5 melanoma cells. Furthermore, PH-894 treatment resulted in a statistically significant upregulation of MART-1 mRNA and protein in these cells. BRD4 silencing and MART-1 upregulation persisted through at least 7 days post-treatment with PH-894. Conclusions: This study demonstrates the ability of PH-894 to efficiently silence BRD4 and upregulate MART-1, thereby increasing the antigenicity of melanoma cells. Local treatment with PH-894 is a potential strategy to decrease BRD4 expression and increase immune response to cancer cells while reducing toxicities associated with systemic BETi. This study supports further development of PH-894 for injectable solid tumor indications such as melanoma. Citation Format: Brianna Rivest, Melissa Maxwell, Andrew Boone, Benjamin Cuiffo, Dingxue Yan, James Cardia. INTASYL™ PH-894 self-delivering RNAi targeting BRD4 enhances the antigenicity of melanoma cells through MART-1 upregulation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C109.
Evidence indicates that diacylglycerol kinases (DGK) are promising targets for the optimization of T cell activity, for example in the setting of adoptive cell therapy (ACT). The tumor microenvironment (TME) of human renal cell carcinoma (RCC) is an immunosuppressive setting where T and NK cell functionality is blocked. DGK–α is a negative regulator of TCR signaling, functioning by metabolizing diacylglycerol to phosphatidic acid and thereby limiting the activation of MAPK/ERK1/2 signaling pathway. DGK-α is found increased in tumor-infiltrating lymphocytes (TIL) from RCC patients and also in adoptively transferred T cells after infiltrating into the TME.1 We previously reported that inhibition of DGK-α restored functionality of unresponsive CD8 T cells and NK cells from RCC-TIL. Other studies demonstrated that knockdown or pharmacologic inhibition of DGK-α and DGK-ζ alone or together increased target cell killing and cytokine production, and protected T cells from inhibitory factors in the TME.2 However, there are no inhibitors for DGK-ζ and available DGK-α inhibitors have undesired pharmacokinetic/pharmacodynamic properties and are highly toxic precluding their clinical application. Here, we present data using a novel RNA interference (RNAi) technology that can specifically target each DGK isoform.
Materials and Methods
INTASYL™ compounds incorporate drug-like properties into RNAi, resulting not only in enhanced cellular uptake in the presence of serum but also eliminating the need for further transfection reagents. Toxicity of compounds applied alone or in combination was assessed by 7-AAD flow cytometry analysis and WST assay. Silencing of mRNA and protein was analyzed by RT-qPCR and SimpleWestern. Downstream signaling pathways and T cell function were analyzed to demonstrate pharmacological efficacy.
Results
Two DGK-ζ compounds and one DGK-α compound were analyzed using Jurkat T cells and primary human TCR-transduced T cells. No effects were seen on cell viability for the compounds applied alone or in combination. On-target knockdown was achieved in Jurkat T cells evidenced by RT-qPCR and SimpleWestern. Silencing of mRNA and protein occurred quickly after 24h, peaked between 48h and 72h and lasted at least for 96h. Stimulation under DGK-targeting INTASYL treatment resulted in enhanced levels of phosphorylated ERK1/2 and enhanced secretion of IL-2.
Conclusions
INTASYL™ self-delivering RNAi compounds represent a promising approach to target intracellular immune checkpoints such as DGKs. The good toxicity profile allows for combined application of several compounds enabling targeting of multiple checkpoints, which likely is necessary to counteract the complex and heterogeneous inhibitory influences of the TME. The technology enables the anti-tumor activity of T and NK cells for immunotherapy, and can be used in ACT and direct therapeutic applications towards the TME.
References
Moon EK, Wang L-C, Dolfi DV, Wilson CB, Ranganathan R, Sun J, et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res 2014;20(16):4262–73. Jung I-Y, Kim Y-Y, Yu H-S, Lee M, Kim S, Lee J. CRISPR/Cas9-mediated knockout of DGK improves antitumor activities of human T cells. Cancer Res 2018;78(16):4692–703.
Disclosure Information
A.S. Herbstritt: C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Significant; Phio Pharmaceuticals. M. Maxwell: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. D. Yan: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. B. Cuiffo: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. J. Cardia: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. S.P. Fricker: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. E. Noessner: C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Significant; Phio Pharmaceuticals.
Adoptive Transfer of antigen specific T cells (ATT) is a powerful tool in the treatment of cancer. However, there are still hurdles to satisfactory efficacy.1 One of them is the upregulation of immune-inhibitory receptors like programmed cell death protein 1 (PD-1). Silencing PD-1 at the mRNA level would not only prevent expression and therefore the inhibitory interaction with its ligand PD-L1, but also inhibit tonic signalling.2 This should increase proliferation, cytotoxicity, cytokine production and metabolic activity via the AKT pathway. Another well-known hurdle to ATT efficacy is the poor persistence of effector T cells in patients. Stem-like memory subsets of CD8 T cells such as those marked by TCF-1 expression may therefore represent an advantageous effector population for ATT, as they show longer persistence, higher proliferative activity, responsiveness to checkpoint inhibitors and the ability to differentiate into new effector T cells.3 Increasing the proportion of this population is thought to be beneficial in anti-tumor therapy. Here, we present data showing that specific downregulation of PD-1 using a novel RNA interference (RNAi) technology increases the frequency of a CD8 T cell population with a stem-like associated marker profile.
Materials and Methods
INTASYL™ compounds incorporate drug-like properties into RNAi, resulting not only in enhanced cellular uptake but also eliminates the need for transfection reagents. TCR53-transduced T cells, suitable for ATT, were incubated with PD-1 targeting INTASYL compound PH-762 for 24h. As controls, cells were either treated with a non-targeting compound (NTC) or left untreated (UTC). Following PH-762 loading, T cells were co-cultured with the autologous tumor cell line RCC-53 for 96h. PD-1 knockdown efficacy was assessed along with other markers of interest via flow cytometry before and after co-culture.
Results
PH-762 treatment reduced PD-1 surface expression in TCR53 T cells after 24h by ~50% compared to UTC or NTC. PH-762 mediated PD-1 silencing increased the subset of TCF-1 positive T cells at 24h post compound treatment and continued through 96h of co-culture with tumor cells. The TCF-1 positive cells expressed stem-like markers including higher expression levels of CD127 and CCR7 together with CD95 and lower levels of perforin.
Conclusions
Increasing the proportion of stem-like CD8 T cells holds promise for optimizing ATT. PD-1 knockdown in TCR53 CD8 T cells for ATT by PH-762 induced the emergence of a T cell population expressing stem-like phenotypic markers including TCF-1. Further experiments are underway to assess the effects of the induced stem-like properties on a functional level, including proliferative activity and effector cell differentiation.
References
Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J 2021;11(4):69. Fernandes RA, Su L, Nishiga Y, et al. Immune receptor inhibition through enforced phosphatase recruitment. Nature 2020;586(7831):779–84. Siddiqui I, Schaeuble K, Chennupati V, et al. Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy. Immunity 2019;50(1):195–211.e10.
Disclosure Information
A.S. Herbstritt: C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Significant; Phio Pharmaceuticals. M. Maxwell: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. D. Yan: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. B. Cuiffo: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. J. Cardia: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. S. Zhou: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. S.P. Fricker: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. E. Noessner: C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Significant; Phio Pharmaceuticals.
Abstract The clinical success of immune checkpoint blockade (ICB) antibodies like those inhibiting PD-1 have revolutionized cancer care, however, durable responses are still limited. Systemic ICB can also elicit immune-related adverse effects (irAEs) whereas local intratumoral (IT) delivery has the potential to mitigate these toxicities. The INTASYL™ platform is a self-delivering RNAi technology that (1) provides efficient delivery into target cells without specialized formulations, mechanical perturbation, or drug delivery systems; and (2) specifically and durably silences target gene expression and (3) has been shown to be safe and effective in clinical applications following local administration. Here we demonstrate that IT treatment with the PD-1 targeting INTASYL PH-762 inhibits tumor growth in a dose dependent fashion in two tumor models, Hepa1-6 and CT26. Modulation of key immune cell populations in the tumor microenvironment (TME) by systemic antibody PD-1 inhibition are recapitulated under IT treatment with the PD-1 targeting INTASYL PH-762. Hepa1-6 or CT26 tumor cells were implanted subcutaneously into female C57BL/6 or BALB/c mice, respectively. Vehicle, non-targeting control (NTC-647) or murine PD-1 targeting INTASYL (mPH-762) were each administered IT at doses ranging from 0.02 - 2 mg/dose; murine anti-PD-1 monoclonal antibody (anti-PD-1 mAb) was administered intraperitoneally (IP) at 200 μg/dose, each on Days 1, 3, 7, 10 and 14. Tumor volumes and body weight were recorded. Tumors (N = 6/group) were isolated from the Hepa1-6 model for ex vivo analyses. All treatments were well tolerated. Treatment with mPH-762 inhibited tumor growth in Hepa1-6 in a dose dependent manner compared to PBS or NTC, with doses of 0.5 mg or 2 mg inhibiting tumor growth similar to anti-PD-1 mAb. In the TME, treatment with mPH-762 modulated tumor immune populations toward antitumor phenotypes, including significantly increasing overall %CD45+ cells and CD8+ T cells, reducing putative Tregs, and increasing median M1/M2 tumor associated macrophage ratios compared to PBS or NTC-647 in a dose associated manner and similar to anti-PD-1 mAb. Dose-correlating on-target silencing of PD-1 protein expression was observed under treatment with mPH-762 but not anti-PD-1 mAb across key TME cell populations. In conclusion, in vivo tumor control elicited by the PD-1 silencing INTASYL mPH-762 (IT) was akin to that provided by systemic anti-PD-1 mAb (IP). Similar modulation of TME immune cell populations associated with antitumor efficacy were observed under both systemic Ab and local INTASYL (IT) treatments. As INTASYL is efficacious and may mitigate irAEs caused by antibody ICB, INTASYL PH-762 warrants further investigation in patients. Citation Format: Benjamin Cuiffo, Melissa Maxwell, Dingxue Yan, James Cardia, Simon P. Fricker. Intratumoral INTASYL™ self-delivering RNAi targeting PD-1 provides in vivo tumor control and mechanistic modulation of tumor microenvironment analogous to that of systemic anti-PD-1 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1739.
