On April 10, 2021 Greenwich LifeSciences, Inc. (Nasdaq: GLSI) (the "Company"), a clinical-stage biopharmaceutical company focused on the development of GP2, an immunotherapy to prevent breast cancer recurrences in patients who have previously undergone surgery, reported a poster of the final 5 year GP2 Phase IIb clinical trial immune response data at the 2021 AACR (Free AACR Whitepaper) Annual Meeting (Press release, Greenwich LifeSciences, APR 10, 2021, View Source [SID1234577823]). Immune response is the primary mechanism of action for GP2 and is critical to developing dosing and booster treatment strategies that are designed to achieve and sustain peak immunity, as well as to prevent metastatic breast cancer recurrences.

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It has been previously reported that the completion of the GP2+GM-CSF Primary Immunization Series (PIS) reduced recurrence rates to 0% over a 5 year follow-up period in HER2 3+ patients who had received a standard course of trastuzumab after surgery. The abstract and poster present the final immune response results over the 5 year follow-up period, assessing peak immunity compared to baseline and between patients treated with GP2+GM-CSF versus GM-CSF alone, including by HER2 status.

Summary of the Final 5 Year Immune Response Data as Previously Presented:

Potent immune response data supports the previously reported clinical outcome of 0% metastatic breast cancer recurrences over 5 years of follow up, if a patient completes the Primary Immunization Series over the first 6 months of GP2 treatment.
Statistically significant peak immunity was reached after 6 months of GP2 treatment as measured in both the Dimer Binding Assay and the DTH skin test.
HER2 3+ population immune response was similar to the HER2 1-2+ population immune response, suggesting the potential to treat the HER2 1-2+ population (including triple negative breast cancer) with GP2 immunotherapy in combination with trastuzumab (Herceptin) based products and other clinically active agents.
Broad based immune response suggests that GP2 immunotherapy and Herceptin based products may also have the potential to treat other HER2 1-3+ expressing cancers.
Dr. Thompson commented, "The analysis of the immune response data in the Phase IIb trial provides mechanistic confirmation of treatment effect correlated with the clinical response previously reported. GP2 treated patients, independent of their HER2 status, experienced a potent immune response to GP2, far greater than patients treated with placebo. In addition, this data has provided us with insight that will guide the upcoming Phase III trial. We believe that monitoring immune response will be an important aspect of the Phase III trial."

Excerpts from the AACR (Free AACR Whitepaper) Poster CT183:

Title: Final five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating a time series of immune responses using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer

Each GP2 treated patient was scheduled to receive 6 intradermal injections with GP2+GM-CSF over the first 6 months of treatment as part of the Primary Immunization Series and 4 boosters every 6 months thereafter. Placebo patients received intradermal injections with GM-CSF alone.

Immune responses to GP2 were measured over time using a CD8 T cell dimer binding assay (Dimer Binding Assay) and delayed-type-hypersensitivity (DTH) skin tests. The Dimer Binding Assay detects the percentage of GP2 specific killer T cells that can kill recurring cancer cells. The DTH skin test measures the diameter of the skin immune response to GP2 in millimeters 48-72 hours after injection of GP2 without GM-CSF.

Figure 1 of the poster shows that GP2 immunity peaked at 6 months in HER2 3+ patients after they completed their first 6 immunizations, as measured by the Dimer Binding Assay. The data also shows that for the 2.5 years that the immune response was measured, the immunity was sustained and remained above baseline, resulting in 100% disease free survival (0% recurrence rate) over 5 years. In the placebo arm, the immune response was not as robust, resulting in 89% disease free survival (11% recurrence rate). Immune response in GP2-treated patients increased quickly during the Primary Immunization Series and remained statistically significantly above baseline for 6 months after the completion of the Primary Immunization Series. Some patients received boosters beginning at 12 months and the immune response was assessed one month after the receiving the booster.

Dimer Binding Assay: The Dimer Binding Assay detects the percentage of GP2 specific killer T cells that can kill recurring cancer cells. Ex vivo immune response was assessed over 2.5 years with blood draws at baseline, then after the 3rd and 6th immunizations in the Primary Immunization Series, and then after each booster. Immune responses were assessed by phenotypic clonal expansion assays in the majority of patients (n=113). GP2-specific CTLs were quantified in patients treated with GP2 using the Ig:A2 Dimer Assay and demonstrated an expansion over time, showing an increase over baseline after the 3rd immunization and remaining elevated for the entire course of follow-up.

Figure 2 of the poster shows the same Dimer Binding Assay data for HER2 3+ patients as in Figure 1, where the GP2 treated patients showed statistically significant dimer readings versus baseline (pre-vaccination) at 3, 6, and 12-13 months.

DTH Skin Test: The DTH skin test measures the diameter of the skin immune response to GP2 in millimeters, 48-72 hours after intradermal injection of GP2 without GM-CSF. A DTH reaction was used to assess in vivo immune responses in patients (n=150). The DTH orthogonal mean of the skin wheal was measured 48-72 hours after injection using the sensitive ballpoint-pen method and is compared using a Wilcoxon Rank-Sum. For GP2 treated patients, there was a significant increase in DTH reactions after the PIS compared to baseline DTH reactions.

Figure 3A shows that after completion of the 6th immunization after 6 months, GP2 treated patients showed a robust immune response using the DTH skin test, while the placebo did not (p = 0.009). Within GP2 treated patients, the change from baseline after 6 months was a median of 4.8 mm (mean of 11.6 mm), which was a statistically significant increase over baseline (p < 0.0001). The change from baseline in DTH at 6 months was more robust in the GP2 treated patients. Those patients had an 11.6 mm mean increase in DTH after 6 months of exposure while patients treated with GM-CSF alone had a 5.2 mm mean increase (p = 0.023). This DTH data supports the Dimer Binding Assay data that shows a peak immune response after 6 months.

Figure 3B shows that the DTH immune response for GP2 treated patients was similarly robust in HER2 3+ patients and HER2 1-2+ patients, independent of prior trastuzumab treatment and HER2 expression levels. Thus, GP2’s robust immune response in the HER2 1-2+ population suggests the potential to apply GP2 immunotherapy to HER2 low to intermediate expressing breast cancers, as well as to other HER2 1-3+ expressing cancers.

AACR Abstract CT183:

Title: Final five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating a time series of immune responses using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer

Snehal S Patel, David B McWilliams, Mira S Patel, Christine T Fischette, Jaye Thompson and F Joseph Daugherty.

Greenwich LifeSciences, Stafford, TX

Background: The final analysis of the GP2 prospective, randomized, placebo-controlled, single-blinded, multicenter Phase IIb trial (NCT00524277) investigating GP2+GM-CSF versus GM-CSF alone in HLA-A02 patients administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with HER2 status (IHC 1-3+) is now complete with 5 year follow-up. It has been previously reported that completion of the GP2+GM-CSF Primary Immunization Series (PIS) reduced recurrence rates to 0% over a 5 year follow-up period in HER2 3+ patients, who received a standard course of trastuzumab after surgery. Here we present the final immune response results, assessing peak immunity compared to baseline and between GP2 treated patients versus placebo, including by HER2 status. Interim analyses for this trial have been previously reported by Mittendorf et al.

Methods: Each GP2-treated patient was scheduled to receive 6 GP2+GM-CSF intradermal injections over the first 6 months as part of the PIS and 4 GP2+GM-CSF booster intradermal injections every 6 months thereafter. Placebo patients received GM-CSF only intradermal injections. Immune responses to GP2 were measured over time using delayed-type-hypersensitivity (DTH) skin tests and CD8 Tcell dimer binding assays.

Results: This basket trial explored HER2 3+ patients, who received a standard course of trastuzumab after surgery, and HER2 1-2+ patients, who did not receive trastuzumab after surgery. A DTH reaction was used to assess in vivo immune responses in patients (n=145). The DTH orthogonal mean was measured 48-72 hours after injection using the sensitive ballpoint-pen method and are compared using a Wilcoxon Rank-Sum. For GP2 treated patients, there was a significant increase in DTH reactions after the PIS compared to baseline DTH reactions. The DTH orthogonal mean in GP2 treated patients at baseline had a median 0.0mm versus 10.8mm after the PIS. For patients receiving GM-CSF alone, the DTH orthogonal mean prior to and after the PIS had a median of 0.0mm. In addition, the DTH reactions after the PIS were significantly greater in GP2 treated patients than in placebo patients (10.8mm vs. 0.0mm, p=0.009) and the DTH immune response in GP2 treated patients was similar between HER2 3+ and HER2 1-2+ patients. Ex vivo immune responses were assessed by phenotypic clonal expansion assays in the majority of patients (n=114). GP2-specific CTLs were quantified using the Ig:A2 dimer assay and demonstrated a gradual expansion over time reaching statistical significance approximately 6 months after the PIS compared to baseline in the GP2 treated patients (n=53, p=0.010) but not in the control patients (n=39, p=0.165).

Conclusions: Immunological data comparing peak immunity to baseline and GP2 treated patients to placebo showed that GP2 treated patients, independent of HER2 status, experienced a significant increase in their immune response while those receiving GM-CSF only did not. Future studies may explore the use of immune responses to assess: immunogenicity of GP2 by HLA type, timing of boosters to sustain immunity, clinical site performance, and the discontinuation of treatment for non-responders.

About the AACR (Free AACR Whitepaper) Annual Meeting 2021

The AACR (Free AACR Whitepaper) is the first and largest cancer research organization dedicated to accelerating the conquest of cancer and has more than 48,000 members residing in 127 countries and territories. The AACR (Free AACR Whitepaper) Annual Meeting program covers the latest discoveries across the spectrum of cancer research — from population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy — and highlights the work of the best minds in research and medicine from institutions all over the world.

About Breast Cancer and HER2/neu Positivity

One in eight U.S. women will develop invasive breast cancer over her lifetime, with approximately 266,000 new breast cancer patients and 3.1 million breast cancer survivors in 2018. HER2/neu (human epidermal growth factor receptor 2) protein is a cell surface receptor protein that is expressed in a variety of common cancers, including in 75% of breast cancers at low (1+), intermediate (2+), and high (3+ or over-expressor) levels.

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 ImmunoGen Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that a poster highlighting preclinical data for its novel ADAM9-targeting ADC, IMGC936, which is being investigated in multiple solid tumor types, is being presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting April 10-15, 2021 (Press release, ImmunoGen, APR 10, 2021, View Source [SID1234577856]).

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"ADAM9 is overexpressed in a wide range of solid tumors and minimally expressed on normal tissue, which makes it an ideal ADC target," said Eric Westin, MD, Vice President, Clinical Development and Translational Sciences at ImmunoGen. "IMGC936 showed compelling anti-tumor activity against multiple patient-derived xenograft models with clinically relevant levels of ADAM9 and was well-tolerated across all models tested. We continue to enroll patients in our Phase 1 dose-escalation study of IMGC936 in multiple tumor types and look forward to sharing initial data by the end of 2021 or early 2022."

POSTER PRESENTATION

Title: "IMGC936, an investigational ADAM9-targeting antibody-drug conjugate, is active against patient-derived ADAM9-expressing xenograft models"
Day/Time: Saturday, April 10, 2021 at 8:30 AM ET
Session Category: Immunology
Session Title: PO.IM02.10 – Therapeutic Antibodies, Including Engineered Antibodies
Abstract: 1841
Additional information can be found at www.aacr.org.

ABOUT IMGC936
IMGC936 is a first-in-class ADAM9-targeting antibody-drug conjugate (ADC) that is comprised of a humanized antibody engineered to include a YTE mutation for enhanced exposure through improved recycling, a tri-peptide cleavable linker stable in circulation, and a next-generation DM21 maytansinoid payload, which is more potent and hydrophobic, resulting in increased bystander activity.

ADAM9 is a cell surface protein that belongs to the ADAM (a disintegrin and metalloproteinase) family of proteases, which have been implicated in cytokine and growth factor shedding and cell migration. Dysregulation of ADAM9 has been involved in tumor progression and metastasis, as well as pathological neovascularization. ADAM9 is overexpressed in multiple solid tumor types (e.g., non-small cell lung, gastric, pancreatic, triple-negative breast, and colorectal cancers) and minimally expressed on normal tissue, making ADAM9 an attractive target for ADC development.

IMGC936 is being co-developed with MacroGenics and is currently in a Phase 1 study enrolling patients with solid tumors that express ADAM9.

On April 10, 2021 Jubilant Therapeutics Inc., a biopharmaceutical company advancing oral, small molecule modulators to address unmet medical needs in oncology and autoimmune diseases, reported that preclinical data from two programs evaluating the company’s PRMT5 inhibitor and PD-L1 inhibitor as anti-cancer agents, will be presented today in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting taking place virtually from April 10-15, 2021 (Press release, Jubilant Therapeutics, APR 10, 2021, View Source [SID1234577872]).

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"We are excited to announce these important data from our PRMT5 and our PD-L1 programs that show efficacy and tolerability in preclinical models," said Syed Kazmi, President and Chief Executive Officer of Jubilant Therapeutics Inc. "Our oral PRMT5 inhibitor has good plasma and sustained brain exposure which results in strong target inhibition, tumor growth delay and survival advantage in both xenografts and orthotopic brain models. Our oral anti-PDL1 immunotherapeutics, with a shorter half-life, are an attractive alternative to current intravenous antibody therapies especially in the maintenance settings with potential to limit immune-mediated toxicities and side effects via innovative dosing approaches, while maintaining the class-based wide anti-tumor efficacy. We look forward to continuing our work on these programs as we see great potential for treating multiple cancers."

A link to the e-posters, listed below, is available through the AACR (Free AACR Whitepaper) website.

Title: Novel, small molecule PRMT5 inhibitors for treatment of cancer
Poster Number: 1128
Date and Time: April 10, 2021 at 8:30 a.m. Eastern Daylight Time (EDT)
Session Title: Epigenetic Targets
Presenter: Dhanalakshmi Sivanandhan, et al.

Title: Novel, small molecule inhibitors of PD-L1/PD-1 interaction
Poster Number: 1630
Date and Time: April 10, 2021 at 8:30 a.m. Eastern Daylight Time (EDT)
Session Title: Immune Checkpoints
Presenter: Dhanalakshmi Sivanandhan, et al.

PRMT5 over-expression, shown in several cancers including lymphoid, lung, breast, glioblastoma, gastric etc., is thought to be an important factor in its tumorigenicity due to its repressive function on tumor suppressor gene expression. Key highlights from an evaluation which examined the tumor growth inhibition of PRMT5 inhibitor JBI-778 in multiple cancer cell lines as well as glioblastoma, include the following:

JBI-778 is a potent PRMT5 inhibitor that is selective against other PRMTs;
JBI-778 shows potent anti-proliferative activity against a number of cancers;
This oral small molecule demonstrated anti-tumor efficacy in a Mantle Cell lymphoma model with an ED50 of < 10 mg/Kg and a complete tumor growth inhibition (97%) at a dose of 50mg/kg; and
JBI-778 exhibited sustained brain exposure and significant tumor growth inhibition in an orthotopic glioblastoma model, translating into substantial survival advantage.
JBI-778 is currently being evaluated for the treatment of multiple cancers and IND-enabling studies have commenced.

PD-L1 expression is an immune evasion mechanism exploited by many cancers, such as melanoma, non-small cell lung cancer and breast cancer, which permits cancer progression and metastasis. Key highlights from the PD-L1/PD-1 study which examined the ability of JBI-1527 to inhibit PD-L1 and restore T-cell proliferation and function, include the following:

JBI-1527 is a potent, selective inhibitor of PD-L1 which induces dimerization of the protein thereby alleviating PD-L1-induced suppression of T cell activation;
The inhibitor shows similar modulation of cytokines as Pembrolizumab in BioMAP assay and competes with anti-PD-L1 blocking antibody suggesting similar binding site on PD-L1; and
In CT-26 and MC38-hPD-L1 syngeneic models, the small molecule showed strong tumor growth inhibition comparable to anti-PD-L1 mAb/Atezolizumab, and was well tolerated.
Studies to further assess JBI-1527 and additional compounds are underway.

Jubilant Therapeutics Inc. is developing a pipeline of novel, differentiated therapeutic assets; for partnership opportunity inquiries please contact [email protected].

On April 10, 2021 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biopharmaceutical company focused on novel and targeted oncology therapies, reported a data update on the safety and tolerability of twice daily (BID) administered poziotinib in NSCLC patients with EGFR or HER2 exon 20 insertion mutations (Press release, Spectrum Pharmaceuticals, APR 10, 2021, View Source [SID1234577824]). These preliminary data, from Cohort 5 of the ZENITH20 clinical trial, continue to show improved tolerability with BID dosing, reduced dose interruption compared to once daily (QD) dosing, and a reduction in treatment emergent Grade 3 or higher adverse events. The preliminary data also demonstrate improved anti-tumor activity with 8mg BID dosing. The presentation is part of the AACR (Free AACR Whitepaper) Virtual Meeting 2021 taking place April 10-15, 2021.

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"The 8mg BID dosing arm is showing the best performance we have seen across the various dosing arms for a mixed population of EGFR and HER2 exon 20 insertion mutations in NSCLC patients. There is clearly an improved therapeutic effect and a lower adverse event rate which is highly encouraging," said Francois Lebel, M.D., Chief Medical Officer of Spectrum Pharmaceuticals. "We are currently expanding the 8mg BID dataset and look forward to evaluating this dose in additional NSCLC patients and other solid tumors."

A copy of the AACR (Free AACR Whitepaper) presentation titled "Poziotinib administered twice daily improves safety and tolerability in patients with EGFR or HER2 exon 20 mutations" is available on Spectrum’s website at View Source

ZENITH20 Trial Design and Preliminary Safety and Efficacy Data for Cohort 5

Cohort 5 of the ZENITH20 trial includes previously treated NSCLC patients with EGFR or HER2 exon 20 insertion mutations. This cohort is investigating the efficacy of poziotinib with various dosing levels including BID administration. For the 38 patients randomized to poziotinib 16mg QD or 8mg BID in Cohort 5, improved responses were reported in the BID arm with 31.6% of patients (6/19) reaching a partial response. For the 38 patients randomized to poziotinib 12mg QD or 6mg BID, these dosing levels were not as active as 8mg BID but showed improved tolerance with BID dosing relative to QD dosing.

Improved tolerability was also observed for the typical TKI related adverse events, with a clinically meaningful reduction in Grade 3 or higher adverse events for the 8mg BID dose relative to 16mg QD. In addition, there were fewer dose interruptions and dose reductions for the BID arms relative to the same QD dose. Cohort 5 is now enrolling exclusively in the 8mg BID arm and data collection is ongoing.

About Poziotinib

Poziotinib is a novel, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that inhibits the tyrosine kinase activity of EGFR as well as HER2 and HER4. Importantly this, in turn, leads to the inhibition of the proliferation of tumor cells that overexpress these receptors. Mutations or overexpression/amplification of EGFR family receptors have been associated with a number of different cancers, including non-small cell lung cancer (NSCLC), breast cancer, and gastric cancer. The company holds an exclusive license from Hanmi Pharmaceuticals to develop, manufacture, and commercialize poziotinib worldwide, excluding Korea and China. Poziotinib is currently being investigated by the company and Hanmi in several mid-stage trials in multiple solid tumor indications.