On April 10, 2021 Kezar Life Sciences, Inc. (Nasdaq), a clinical-stage biotechnology company discovering and developing breakthrough treatments for immune-mediated and oncologic disorders, reported preclinical data on the company’s novel protein secretion program during two poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Virtual Annual Meeting (Press release, Kezar Life Sciences, APR 10, 2021, View Source [SID1234577844]).

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"The growing body of evidence generated by our team supports the strong therapeutic potential of inhibiting Sec61 and the protein secretion pathway as a way to generate novel therapies to treat multiple tumor indications," said Christopher Kirk, PhD, Kezar’s President and Chief Scientific Officer. "These data provide a robust scientific framework for identifying which tumor types might be the most sensitive to inhibition of the Sec61 translocon and the protein secretion pathway."

Kezar examined the activity of KZR-261, a small molecule inhibitor of the Sec 61 translocon, and a closely related representative molecule in hundreds of tumor cell lines. The objective was to compare drug activity and identify sensitivity to gene mutations and impact on gene expression levels. No single gene predicted the activity of KZR-261, consistent with the known impact of KZR-261 on multiple targets. However, representative gene modules identified through mechanism agnostic analysis were associated with sensitivity in tumor cells and show high overlap with key processes involved in protein secretion. Analyses of primary tumor and tissue expression datasets predict that many tumor types will be more sensitive than normal tissues and cells. Data from these analyses will inform selection of tumor types for study in future clinical trials.

Global proteomic profiling of protein secretion in tumor cells and non-transformed cells was also conducted. KZR-261 and the related molecules reduce expression of Sec61 clients, namely secreted and transmembrane proteins. In tumor cells, these compounds reduced expression of approximately 10% of Sec61 clients by at least two-fold. However, in non-transformed cells, KZR-261 inhibited the expression of less than 5% of measured Sec61 clients, many of which can be measured from clinical samples in future clinical trials.

Pending successful completion of drug product manufacturing, submission of an Investigational New Drug (IND) application is anticipated in mid-2021. A first-in-human Phase 1 study to evaluate the safety and anti-tumor activity of KZR-261 in patients with solid tumors is expected to commence shortly thereafter.

Details on Kezar’s poster presentations at AACR (Free AACR Whitepaper) are as follows:

Title: Prioritizing tumor types for clinical study of novel Sec61 inhibitors by searching for expression profiles of sensitive cell lines in tumor sample databases
Presenter/s: Eric Lowe, R. Andrea Fan, Henry W. B. Johnson, Christopher J. Kirk, Dustin McMinn, Yu Qian, Brian Tuch
Session: Genomic Profiling of Tumors – Abstract #2226
Date and time: Available on demand [8:30AM ET, Saturday, April 10, 2021]

Title: Quantitative proteomic profiling of novel anti-cancer small molecule inhibitors of Sec61: Mechanistic investigation and biomarker discovery
Presenter/s: Yu Qian, Jennifer Whang, Janet Anderl, Andrea Fan, Henry W. B. Johnson, Christopher J. Kirk, Eric Lowe, Dustin McMinn, Beatriz Millare, Tony Muchamuel and Jinhai Wang; Kezar Life Sciences
Session: Proteomics and Biomarker Discovery – Abstract #2816
Date and time: Available on demand [8:30AM ET, Saturday, April 10, 2021]

The posters are available in the "Our Science" section of kezarlifesciences.com.

About KZR-261

KZR-261, a novel, first-in-class protein secretion inhibitor, is the first clinical candidate to be nominated from Kezar’s research and discovery efforts targeting protein secretion pathways. KZR-261 is a broad-spectrum anti-tumor agent that acts through direct interaction and inhibition of Sec61 activity. The compound was discovered by Kezar through a robust medicinal chemistry campaign in which several scaffolds were progressed through the company’s proprietary platform evaluating Sec61 modulation. As a result, Kezar has established a broad library of protein secretion inhibitors. KZR-261 has demonstrated several encouraging properties that lead to its potential to be an anti-cancer agent for the treatment of solid and hematologic malignancies. An IND submission in solid tumors is expected to be filed in mid-2021.

On April 10, 2021 Elevation Oncology, a clinical stage biopharmaceutical company focused on the development of precision medicines for patients with genomically defined cancers, reported the presentation by its collaborators in the Marc Ladanyi lab at Memorial Sloan Kettering (MSK) of further preclinical data on the specific inhibition of NRG1 fusion-induced tumorigenesis and signaling by seribantumab, a HER3 monoclonal antibody, at the American Association of Cancer Research Virtual Annual Meeting 2021 (Press release, Elevation Oncology, APR 10, 2021, View Source [SID1234577841]). These data (Odintsov et al., 2021) in patient-derived xenograft (PDX) models of NRG1 fusion-positive pancreatic and cholangiocarcinoma build on earlier studies generated in lung and ovarian NRG1 fusion PDX models, recently published in Clinical Cancer Research, and further support the mechanistic rationale for the Phase 2 CRESTONE study for patients with solid tumors of any origin harboring an NRG1 gene fusion. The CRESTONE study is currently enrolling at sites across the United States.

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"Here we observed that NRG1 fusions activated HER3 and downstream signaling mediators such as AKT in a pancreatic cell line," said Igor Odintsov, MD, Research Fellow at MSK and lead author of the poster presentation. "Treatment with seribantumab was able to inhibit phosphorylation of the activated HER3 and AKT in the same cell line, and subsequent treatment of an APP-NRG1 fusion-positive pancreatic PDX model with seribantumab robustly inhibited tumor growth at clinically achievable doses."

Regressions were observed in all mice treated with 10 mg/kg BIW seribantumab, equivalent to a clinical dose of 2.6 g seribantumab in humans by allometric scaling. As in prior analysis in lung and ovarian NRG1 fusion PDX models, the pan-ERBB inhibitor afatinib was used as an active control in this pancreatic PDX model. No regression was observed in pancreatic PDX tumors treated with afatinib at 5 mg/kg QD.

NRG1 fusions have been identified in a variety of solid tumors, including lung, pancreatic, gallbladder, breast, ovarian, colorectal, neuroendocrine, cholangiocarcinomas, and sarcomas. Current data suggest that NRG1 fusions are predominantly mutually exclusive with other known driver alterations and are therefore considered to be the primary driver of the tumor’s growth and proliferation.

"The rarity of competing oncogenic drivers in tumors driven by an NRG1 fusion presents a strong biological rationale for use of a targeted anti-HER3 monotherapy approach across tumor types. This approach is reflected in the design of our Phase 2 CRESTONE study as a tumor-agnostic study of monotherapy seribantumab with pre-defined exclusion of patients whose tumors harbor multiple actionable driver alterations," said Shawn M. Leland, PharmD, RPh, Founder and Chief Executive Officer of Elevation Oncology. "In rare instances when multiple actionable driver alterations are identified in the same tumor, we believe there may be a similar biological rationale for addressing each driver alteration through combinations of agents targeted to each individual alteration, rather than the traditional combinations with chemotherapy. We are excited to report early results from preclinical exploration of this hypothesis, and look forward to continued investigation of new treatment paradigms informed by comprehensive genomic profiling of tumors."

"We utilized an RBPMS-NRG1 fusion cholangiocarcinoma PDX model that also contained mutations in both ERBB4 and IDH1," continued Dr. Odintsov. "While treatment with monotherapy seribantumab or afatinib in this model produced mixed results, by applying a triple combination of seribantumab with afatinib to target the entire ERBB family, and AG-120 to target the IDH1 mutation, we were able to achieve regressions in the majority of tumors. This suggests that tumors harboring multiple oncogenic drivers may benefit from combination therapy that addresses the contribution of each genomic alteration in disease progression."

In totality, the data reported support the use of monotherapy seribantumab to treat GI and other cancers that are uniquely driven by an NRG1 fusion in the ongoing Phase 2 CRESTONE study. Patients and physicians can learn more about the CRESTONE study at www.NRG1fusion.com or on www.ClinicalTrials.gov under the NCT number NCT04383210.

On April 10, 2021 Jounce Therapeutics, Inc. (NASDAQ: JNCE), a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, reported new preclinical data on JTX-8064, the first tumor-associated macrophage program from their Translational Science Platform, at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting being held April 10-15, 2021 (Press release, Jounce Therapeutics, APR 10, 2021, View Source [SID1234577840]). The poster presentation includes data showing a high Leukocyte Immunoglobulin Like Receptor B2 (LILRB2) to interferon gamma (IFNγ) ratio is associated with resistance to PD-(L)1 inhibitor treatment in humans, JTX-8064’s ability to bridge innate and adaptive immunity, and how Jounce’s Translational Science Platform informed indication selection for the Phase 1 INNATE trial.

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"The translational analyses presented at AACR (Free AACR Whitepaper) link JTX-8064’s mechanism to tumor types that may respond better to LILRB2 inhibition," said Elizabeth Trehu, M.D., chief medical officer of Jounce Therapeutics. "The Phase 1 INNATE trial is designed to move as quickly as possible to proof of concept and this new data enabled the prioritization of tumor-specific expansion cohorts, which are on track to start enrolling in the second half of 2021. Furthermore, the negative prognostic implications of a high LILRB2 to IFNγ ratio support the role of LILRB2 in resistance to PD-(L)1 inhibitors and highlight the potential for JTX-8064 to reverse this resistance."

In a poster titled "Tumor associated macrophages and resistance to immune checkpoint blockade: Consideration of cancer indications for the clinical development of JTX-8064, an anti-LILRB2/ILT4 monoclonal antibody" Jounce demonstrated:

JTX-8064 can induce T cell activation in co-culture with macrophages, demonstrating its potential to bridge the gap between innate and adaptive immune responses;
CD163+ M2 macrophages co-localize with T cells in the tumor microenvironment, and patients with high levels of LILRB2 or a proprietary tumor-associated macrophage (TAM) signature score relative to an IFNγ signature score are less responsive to PD-(L)1 inhibitors, providing evidence that LILRB2+ macrophages may be involved in mechanisms of primary resistance to PD-(L)1 inhibitors; and
Expression profiles of LILRB2 mRNA, TAM signatures, and other inflammatory cell signatures were used to identify tumor types that may benefit most from JTX-8064 treatment and used to inform indication selection for expansion cohorts of the Phase 1 INNATE trial.
The poster is available on the "Our Pipeline" section of the Jounce Therapeutics website at www.jouncetx.com.

About JTX-8064

JTX-8064 is a humanized IgG4 monoclonal antibody designed to specifically bind to Leukocyte Immunoglobulin Like Receptor B2 (LILRB2/ILT4) and block interactions with its ligands. JTX-8064 is the first tumor-associated macrophage candidate developed from Jounce’s Translational Science Platform. Preclinical data presented at the 2020 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s Annual Meeting and the 2019 and 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meetings support the development of JTX-8064 as a novel immunotherapy to reprogram immune-suppressive macrophages and enhance anti-tumor immunity. A Phase 1 clinical trial named INNATE (NCT04669899), of JTX-8064 as a monotherapy and in combination with either JTX-4014, or pembrolizumab, is currently enrolling patients with advanced solid tumors.

On April 10, 2021 HOOKIPA Pharma Inc. (NASDAQ: HOOK, ‘HOOKIPA’), a company developing a new class of immunotherapeutics based on its proprietary arenavirus platform, reported positive preliminary Phase 1 immunogenicity data for its lead oncology candidates, HB-201 and HB-202, to treat Human Papillomavirus 16-positive (HPV16+) cancers (Press release, Hookipa Biotech, APR 10, 2021, View Source [SID1234577839]). The results are from an ongoing Phase 1/2 study (NCT04180215) currently investigating HB-201 as a single-vector therapy and HB-201 and HB-202 as an alternating two-vector therapy for the treatment of advanced metastatic HPV16+ cancers. The data were presented today at a late-breaker poster session at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting.

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"We’re excited to see the quantity and quality of a targeted immune response, particularly the directly measured increase in HPV16+-specific CD8+ T cells, generated by a single dose of our lead oncology candidates, HB-201 or HB-202. As we are still exploring optimal dosing, these early responses are particularly encouraging," said Joern Aldag, Chief Executive Officer of HOOKIPA. "We believe our novel arenavirus platform has the potential to introduce a new class of immunotherapeutics that could considerably advance how physicians care for people with HPV16+ cancers. Building on the early clinical results reported on HB-201 in December, we look forward to additional data read-outs from our first clinical oncology program in the coming months."

Preliminary data showed a strong antigen-specific T cell response after one dose of HB-201 or HB-202, based on direct Enzyme-Linked ImmunoSpot (ELISpot) T cell analysis. (ELISpot is used to quantify antigen-specific T cells in the blood.) All 5 patients who received a single dose of HB-201 or HB-202 had a strong induction of T cells specific to HPV16+ cancer 2 weeks after administration. An up to 250-fold increase in antigen-specific T cells was observed 2 weeks after a single dose of HB-201 in 4 patients. One patient who received a single dose of HB-202 showed a 150-fold increase in antigen-specific T cells 2 weeks after administration. Importantly, the results are based on direct ELISpot without ex vivo expansion of T cells, underscoring the magnitude of T cell response generated by one dose of HB-201 or HB-202. (Ex vivo expansion is often used to amplify responses so that they are more easily measured.) The data are derived from dose level 2 of ongoing dose escalation, and the recommended Phase 2 doses for HB-201 and HB-202 have not been reached.

In addition, analysis of the antigen-specific T cell response showed an increase in CD8+ T cells specific to HPV16+ cancer after a single dose of HB-201 (baseline 0% to 2.8% two weeks later) and HB-202 (baseline 0% to 8.1% two weeks later). These data were assessed using intracellular cytokine staining (ICS) followed by flow cytometry, which differentiates antigen-specific CD8+ T cells (cytotoxic/killer T cells) from antigen-specific CD4+ T cells (helper T cells). Of note, the HPV16+ cancer patients included in this analysis had negligible levels of antigen-specific CD8+ T cells prior to treatment with HB-201 or HB-202.

Other preliminary immunogenicity data highlight immune system activation following a single dose of HB-201. Blood samples from 12 patients were assessed across 13 timepoints for levels of 30 different cytokines and chemokines, which play critical roles in activating an immune response. At the time of data cut-off, baseline and day 4 samples were available for 9 of the 12 patients. The analysis showed that, 4 days after a single dose of HB-201, interferon-gamma levels increased in 90% of patients, and an increase in other immune stimulatory cytokines and chemokines was observed. These data comprise an early sign of natural killer (NK) cell and/or T cell activation by HB-201.

"Treatment options are limited for people with metastatic HPV16+ cancers, and the likelihood for long-term survival is low," said Dmitriy Zamarin, MD, PhD, Translational Research Director in Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center and co-investigator in this study. "We don’t often see this robust and high-quality immune response, particularly in antigen-specific CD8+ T cells, from a single dose and without any combination therapy. I’m excited to see how these early immunogenicity data may translate to clinical outcomes in the future."

These preliminary immunogenicity data reinforce the promising anti-tumor activity reported from this trial in December 2020 and are consistent with recently published preclinical data, which showed that intravenous HB-201 administration induced single digit percentage of antigen-specific CD8+ T cells, while alternating administration of HB-201 and HB-202 induced a potent CD8+ T cell response, exceeding 50% of the circulating T cell pool. As the HB-201/HB-202 clinical trial is ongoing, HOOKIPA expects to present additional translational and clinical data at upcoming medical conferences in 2021. The company anticipates these data to further inform the HPV program, as well as other earlier stage programs in its oncology pipeline, including therapeutics for prostate cancer, as it seeks to deliver transformational therapies through induction of antigen-specific CD8+ T cells. The poster and audio review are available at View Source

About HB-201/HB-202
HB-201 and HB-202 are HOOKIPA’s lead oncology candidates engineered with the company’s proprietary replicating arenaviral vector platform. Each single-vector compound uses a different arenavirus backbone (LCMV for HB-201 and PICV for HB-202), while expressing the same antigen, an E7E6 fusion protein derived from HPV16. In pre-clinical studies, alternating administration of HB-201 and HB-202 resulted in a ten-fold increase in immune response and better disease control than either compound alone.

About the trial
This Phase 1/2 clinical trial is an open-label trial exploring different dose levels and dosing schedules in individuals with treatment-refractory HPV16+ cancers. The primary endpoint of the Phase 1 is a recommended Phase 2 dose based on safety and tolerability. Secondary endpoints include anti-tumor activity as defined by RECIST 1.1 and immunogenicity.

The trial is evaluating HB-201 as a single-vector monotherapy, as an alternating two-vector therapy with HB-202, and in combination with a PD-1 inhibitor. Participants receive HB-201/HB-202 intravenously or, for patients with an accessible lesion, the first dose can be delivered via intratumoral injection followed by intravenous dosing. Dosing every three weeks and every two weeks is being explored, as well as different dose levels. HOOKIPA expects to share interim clinical data on the HB-201/202 therapy in mid-2021.

About Human Papillomavirus
Human Papillomavirus, or HPV, is estimated to cause about 5 percent of the worldwide burden of cancers. This includes approximately 99 percent of cases in cervical, up to 60 percent of head and neck, 70 percent of vaginal and 88 percent of anal cancers.

The majority of these cancers are caused by the HPV serotype 16. Most infections with HPV are cleared from the body with no lasting consequences. However, in some cases, HPV DNA becomes integrated into chromosomal DNA. When host cells take up this DNA, they express the HPV E6 and E7 proteins. This uptake can potentially lead to cancer since expression of these proteins leads to alterations in cell cycle control, which in turn predisposes these cells to become cancerous.

On April 10, 2021 Arch Oncology, Inc., a clinical-stage immuno-oncology company focused on the discovery and development of anti-CD47 antibody therapies, reported the presentation of new preclinical data on AO-176 in pediatric acute lymphoblastic leukemia (T-ALL) during a late-breaking poster presentation at the AACR (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Arch Oncology, APR 10, 2021, View Source;utm_medium=rss&utm_campaign=arch-oncology-presents-new-preclinical-t-all-data-on-highly-differentiated-anti-cd47-antibody-ao-176-at-aacr-2021 [SID1234577838]). This research was funded by a grant from the National Cancer Institute (NCI), part of the National Institutes of Health, to the Pediatric Preclinical Testing Consortium (PPTC).

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AO-176 is an anti-CD47 antibody with a potential best-in-class profile that works by blocking the "don’t eat me" signal and also by directly killing tumor cells, with preferential binding to tumor versus normal cells. Currently, AO-176 is being evaluated in Phase 1/2 clinical trials for the treatment of patients with select solid tumors and hematologic malignancies, both as monotherapy and in combination with standard therapies.

"At AACR (Free AACR Whitepaper) this year, we are presenting preclinical data in two new hematologic indications, showing AO-176’s strong therapeutic potential in lymphoma and pediatric T-ALL," said Daniel Pereira, Ph.D., Chief Scientific Officer of Arch Oncology. "AO-176 demonstrated significant single-agent in vivo anti-leukemic activity in pediatric T-lineage ALL PDX models. Our antibody delayed disease progression and decreased human leukemia infiltration of murine spleens to increase overall survival in mice inoculated with T-ALL cells, suggesting that targeting CD47 in T-ALL may be a promising therapeutic approach. AO-176 has highly-differentiated mechanisms that show the potential to offer an improved efficacy and safety profile among anti-CD47 agents in development for patients and we are excited to continue to advance this novel therapy in the clinic for patients with solid tumors and hematologic malignancies."

Richard Lock, Ph.D., Lead Investigator for this study and Head of the Blood Cancers Theme and Group Leader of the Leukaemia Biology Group at Children’s Cancer Institute, one of the NCI funded PPTC institutions, added "AO-176 exhibited impressive single-agent in vivo activity for a monoclonal antibody against highly-aggressive experimental models of pediatric T-cell acute lymphoblastic leukemia. Given its novel mechanisms of action and single-agent activity, there is great interest in next testing AO-176 in combination with standard-of-care drugs against experimental models of high-risk pediatric leukemia."

American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021

Late-Breaking Poster Presentation Title: The differentiated CD47 monoclonal antibody AO-176 exhibits significant in vivo activity against xenograft models of pediatric acute lymphoblastic leukemia (ALL) (Abstract # LB171)
Session Category: Immunology
Session Title: Therapeutic Antibodies, Including Engineered Antibodies

Poster Presentation Title: AO-176, a highly differentiated clinical stage anti-CD47 antibody, is efficacious in pre-clinical models of lymphoma (Abstract #954)
Session Category: Experimental and Molecular Therapeutics
Session Title: Biological Therapeutic Agents

Information on the abstracts is available on AACR (Free AACR Whitepaper)’s website.

These poster presentations are available at View Source

About AO-176

AO-176 is a humanized anti-CD47 IgG2 antibody with a potential best-in-class profile. AO-176 is highly differentiated, with the potential to improve upon the safety and efficacy profile relative to other agents in this class of innate checkpoint inhibitors. AO-176 is engineered to block the "don’t eat me" signal, the standard mechanism of anti-CD47 antibodies. Beyond blocking this signal, AO-176 has additional mechanisms, including directly killing tumor cells and inducing DAMPs (damage associated molecular patterns) in preclinical models, resulting in immunogenic cell death. Importantly, in these models AO-176 binds preferentially to tumor cells, instead of to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Publications and presentations on AO-176 can be found at View Source

AO-176 is being evaluated in Phase 1/2 clinical trials for the treatment of patients with select solid tumors and hematologic malignancies, both as monotherapy and in combination with standard therapies. In a Phase 1 trial in solid tumors, AO-176 demonstrated encouraging early tolerability and activity when administered as a single agent. Additional information about these trials may be found at www.clinicaltrials.gov using the trial identification number NCT03834948 (solid tumors) or NCT04445701 (multiple myeloma).