On April 10, 2021 Advaxis, Inc. (Nasdaq: ADXS), a clinical-stage biotechnology company focused on the development and commercialization of immunotherapy products, and Precision for Medicine, a specialized services company supporting next generation approaches to drug development and commercialization, reported data on the development of a novel flow immunophenotyping assay to accurately evaluate total PD-1 expression as a pharmacodynamic marker during PD-1 blockade, and translational data demonstrating immune responses correlated to observed clinical benefit from the Company’s ongoing Phase 1/2 study evaluating ADXS-503 in combination with KEYTRUDA, presented as a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Advaxis, APR 10, 2021, View Source [SID1234577835]). ADXS-503 is the first drug construct from the ADXS-HOT off-the-shelf, cancer-type specific, immunotherapy program which leverages Advaxis’ proprietary Lm technology platform to target hotspot mutations that commonly occur in specific cancer types as well as other proprietary, tumor-associated antigens.

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"These presented data suggest this novel immunophenotyping assay has the potential to more accurately measure pharmacodynamic biomarkers in immunotherapy," said Ken Berlin, Chief Executive Officer of Advaxis. "This assay enables the detection of both free and drug-bound PD-1 expression, independent of PD-1 receptor status or interference due to PD-1 blockade, enabling the accurate evaluation of PD-1 expression in patients undergoing treatment with pembrolizumab. We believe this is another important step forward in further understanding immune responses in patients treated with immunotherapy agents, and may provide important translational insights specific to PD-1 expression and immune modulation which may help shape treatment strategies moving forward."

Mr. Berlin continued, "The flow cytometry data confirmed the on-mechanism activation of the innate and adaptive immune systems in patients with observed clinical benefit following treatment with ADXS-503 in combination with pembrolizumab. The demonstrated proliferation and activation of NK cells and CD8 + T cells, plus increased PD-1 expression in diverse immune cells in patients achieving clinical benefit, add to the growing body of evidence which demonstrate the potential of ADXS-503 to re-sensitize or enhance responses to pembrolizumab, even in patients with prior progression. We will continue these analyses with Precision for Medicine on additional patients from our ongoing Phase 1/2 study in NSCLC, and look forward to continued progress as we build upon our previously reported efficacy results which show promising and durable clinical benefit after treatment with ADXS-503, our first off-the-shelf neoantigen immunotherapy candidate."

Key presentation highlights:

Poster presentation titled, "Evaluation of total PD-1 expression using multi-color flow cytometry in metastatic non-small cell lung cancer patients treated with multi-neoantigen vector (ADXS-503) alone and in combination of pembrolizumab to assess T-cell & T-cell memory subsets" presented by Dr.Venkat Mohanram, Senior Scientist at Precision for Medicine.

A novel multi-color flow cytometry analysis was developed to accurately identify PD-1 expression on peripheral blood mononuclear cells (PBMCs) of NSCLC patients receiving PD-1/PD-L1 blockade therapy with pembrolizumab and ADXS-503

No interference in PD-1 detection due to pembrolizumab blockage was observed, enabling the determination of PD-1 expression independent of PD-1 receptor status, with both free and drug-bound PD-1 detected

Preliminary flow cytometry data demonstrated on-mechanism activation of innate and adaptive immune responses to ADXS-503. Three patients from the ongoing Phase 1/2 with demonstrated clinical benefit of stable disease showed:

Proliferation and activation of NK cells
Increased PD-1 expression on circulating CD4+, CD8+ and NK cells
Increased counts of CD8+ T cells including proliferative, cytotoxic and memory CD8+ T cells
The Phase 1/2 clinical trial of ADXS-503 is seeking to establish the recommended dose, safety, tolerability and clinical activity of ADXS-503 administered alone and in combination with a KEYTRUDA in approximately 50 patients with NSCLC, in at least five sites across the U.S. The two dose levels with monotherapy in Part A, (1 X108 and 5 X108 CFU) have been completed. Part B with ADXS-503 (1 X108 CFU) in combination with KEYTRUDA is currently enrolling its efficacy expansion for up to 15 patients at dose level 1 (1 X108 CFU + KEYTRUDA) with the potential to proceed to dose level 2 (5 X108 CFU + KEYTRUDA) at a later date. Part C, which is evaluating ADXS-503 in combination with KEYTRUDA (1 X108 CFU + KEYTRUDA) as a first line treatment for patients with NSCLC with PD-L1 expression ≥ 1% or who are unfit for chemotherapy is currently enrolling patients.

About ADXS-HOT
ADXS-HOT is a program that leverages the Company’s proprietary Lm technology to target hotspot mutations that commonly occur in specific cancer types. ADXS-HOT drug candidates are designed to target acquired shared or "public" mutations in tumor driver genes along with other proprietary cancer-testes and oncofetal tumor-associated antigens that also commonly occur in specific cancer types. ADXS-HOT drug candidates are an off-the-shelf treatment, designed to potentially treat all patients with a specific cancer type, without the need for pretreatment biomarker testing, DNA sequencing or diagnostic testing.

On April 10, 2021 Harpoon Therapeutics, Inc. (NASDAQ: HARP), a clinical-stage immunotherapy company developing a novel class of T cell engagers, reported the availability of three poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Harpoon Therapeutics, APR 10, 2021, View Source [SID1234577851]). The presentations will be available beginning today at 8:30 a.m. ET through the virtual meeting website at www.aacr.org and on the Harpoon corporate website at www.harpoontx.com.

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Key findings of each of the posters are described below.

FLT3-targeting TriTACs are T cell engagers for treatment of acute myeloid leukemia
Presenter: Richard J. Austin, Ph.D., Abstract #: 2643

FLT3 RNA is found in over 95% of AML samples and FLT3 mutations are oncogenic and found in approximately 30% of AML. This provides the rationale that a FLT3-targeting T cell engager could be a valid therapeutic approach for AML. Data show that FLT3 TriTACs bind human and non-human primate FLT3, and can redirect T cells to kill FLT3 expressing cells in vitro. In addition, FLT3 TriTACs eliminate FLT3 expressing cells in a non-human primate study and are well tolerated after a single dose.

ProTriTAC is a modular and robust T cell engager prodrug platform with therapeutic index expansion observed across multiple tumor targets
Presenter: S. Jack Lin, Ph.D., Abstract #: 933

ProTriTAC is a conditionally active T cell engager platform that is designed to be preferentially active in the tumor. This enables the targeting of more broadly expressed solid tumor targets and allows T cell engagers to address more tumor types. Data presented today illustrate the consistency and the robustness of the ProTriTAC platform in vitro and in vivo as demonstrated by cell-based assays, pharmacokinetic studies in non-human primates, and therapeutic index assessments in tumor-bearing animals across multiple tumor targets. IND-enabling studies are currently underway for Harpoon’s first ProTriTAC program (HPN601).

Combinatorial antitumor effects of CD3-based trispecific T cell activating constructs (TriTACs) and checkpoint inhibitors in preclinical models
Presenter: Mary Ellen Molloy, Ph.D. Abstract #: 1573

TriTAC molecules induce PD1/PD-L1 expression on T cells which may lead to suppression of the cytolytic functions of TriTAC activated T cells. PD1 can be readily detected on T cells subsequent to the engagement of the TCR by the TriTAC molecule. Data presented today show that the combination of HPN536 with a PD-L1 inhibitor led to more potent antitumor activity in an MSLN expressing ovarian cancer xenograft model. Similar enhanced anti-tumor effects were shown in an MSLN expressing lung cancer model for HPN536 in combination with anti-PD1 or an anti-PD1 antibody. These data demonstrate the potential utility of PD1/PD-L1 blockade to enhance the potency of TriTAC mediated tumor cell killing.

"These data from Harpoon’s poster presentations at AACR (Free AACR Whitepaper) underscore the potential for further investigations of additional tumor targets, combination approaches with TriTACs, and conditionally active T cell engager prodrugs, or ProTriTACs, which may lead to greater tumor specificity, enhanced efficacy, and improved tolerability for patients," said Holger Wesche, Ph.D., chief scientific officer of Harpoon Therapeutics. "I am encouraged by these findings and look forward to future validation in the clinic."

On April 10, 2021 Bayer reported Results from the randomized, double-blind, placebo-controlled Phase III trial CHRONOS-3 show a significant improvement in progression-free survival (PFS) with the investigational combination of Aliqopa (copanlisib) and rituximab given intravenously in patients with relapsed indolent non-Hodgkin’s Lymphoma (iNHL) compared to the combination of rituximab and placebo (Press release, Bayer, APR 10, 2021, View Source [SID1234577867]). After a median follow-up of 19.2 months, patients treated with this combination had a median PFS of 21.5 months (95% CI 17.9, 33.0) versus 13.8 months in patients treated with rituximab and placebo (95% CI 10.2, 17.5), (HR=0.52, p=0.000002). No new safety signals were identified for Aliqopa in the combination arm of the study.1 The data will be presented in a Clinical Trials Plenary Session on April 10 at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 and simultaneously published in The Lancet Oncology.

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CHRONOS-3 is a Phase III randomized, double-blind, placebo-controlled trial with the objective to evaluate whether Aliqopa in combination with rituximab is superior to placebo plus rituximab in extending PFS in patients with relapsed iNHL following at least one prior rituximab-containing therapy. Patients who had a progression-free and treatment-free interval of at least 12 months after completion of the last rituximab-containing regimen or patients unwilling/unfit or for who chemotherapy was contraindicated by reason of age, co-morbidities and/or residual toxicity were included.2

In 2017, Aliqopa was approved for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies based on the results of a single-arm, multicenter, Phase II clinical trial (CHRONOS-1).3 Accelerated approval was granted for this indication based on overall response rate (ORR). Continued approval for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial.

"In clinical practice, we have seen an overall improvement in the prognosis of iNHL patients, yet relapsed disease is still a prominent treatment challenge," said Matthew J. Matasar, M.D., Medical Oncologist, Regional Care Network Medical Site Director, Memorial Sloan Kettering Cancer Center (MSK) Bergen. "The results reported with the combination of copanlisib and rituximab suggest a potential advancement for patients with these diverse types of cancers."

"Bayer is committed to putting patients’ needs first and delivering innovative treatment options that address areas of high unmet need, and clinical research is the first step in that process," said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer. "These data highlight the potential of Aliqopa and rituximab as a new strategy for treating these patients and we look forward to advancing regulatory discussions."

Bayer is in discussions with health authorities worldwide regarding the data from CHRONOS-3.

Additional CHRONOS-3 Data Being Presented at AACR (Free AACR Whitepaper)
In addition to the primary endpoint of PFS, data on the secondary endpoints of ORR and complete response rate (CRR) will also be presented. Best ORR for the combination of Aliqopa and rituximab was 80.8% (95% CI 76, 85) versus 47.7% (95% CI 40, 56) for rituximab and placebo (p<0.0001), with 33.9% and 14.6% of patients achieving CR, respectively. Of the relapsed iNHL patients included in the trial, 60% had FL, 20.7% marginal zone lymphoma (MZL), 10.9% small lymphocytic lymphoma (SLL) and 8.3% lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM). Analysis of the subtypes will be presented at AACR (Free AACR Whitepaper) and published in The Lancet Oncology.1

All-grade treatment-emergent adverse events (TEAEs) observed with the Aliqopa and rituximab combination that occurred in more than 20% of the patients included hyperglycemia (69.4%), hypertension (49.2%), diarrhea (33.6%), neutropenia (20.8%), nausea (22.5%) and pyrexia (20.5%). Discontinuation due to all-grade TEAEs in CHRONOS-3 for Aliqopa and rituximab was 32% versus 8% for rituximab and placebo.1

Aliqopa is an intravenous phosphatidylinositol-3-kinase (PI3K) inhibitor with predominant activity against alpha and delta isoforms the PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells.4 Aliqopa is approved in the U.S. under the accelerated approval pathway for the treatment of adult patients with relapsed FL who have received at least two prior systemic therapies. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Accelerated approval was granted for this indication based on an ORR of 59% (n=61/104; 95% CI 49, 68), including 14% (15/104) of CRs from the open-label, single-arm multicenter, Phase II clinical trial (CHRONOS-1), in a total of 142 subjects, which included 104 subjects with follicular B-cell non-Hodgkin’s Lymphoma who had relapsed disease following at least two prior treatments. In the updated two-year follow-up analysis conducted on data until 16 weeks after the last patients eligible for full analysis started treatment, Aliqopa ORR was 59% (n=61; 95% CI 49, 68), including 20% CR (n=21).5 Tumor response was assessed according to the International Working Group response criteria for malignant lymphoma. Efficacy based on ORR was assessed by an Independent Review Committee.

Disclosure: This study was sponsored by Bayer AG. Dr. Matasar has received honoraria from Bayer AG and subsidiaries of Bayer AG for advising and related activities. Bayer AG also provides research funding for Dr. Matasar through Memorial Sloan Kettering Cancer Center (MSK). In addition, Dr. Matasar has received honoraria from Roche/Genentech for advising and related activities, and the company also provides research funding for him through MSK.

About Aliqopa (copanlisib) Injection3
Aliqopa (copanlisib) is indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Aliqopa is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Aliqopa has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Aliqopa inhibits several key cell-signaling pathways, including B-cell receptor signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.

IMPORTANT SAFETY INFORMATION FOR ALIQOPA (copanlisib)

Infections: Serious, including fatal, infections occurred in 19% of 317 patients treated with ALIQOPA monotherapy. The most common serious infection was pneumonia. Monitor patients for signs and symptoms of infection and withhold ALIQOPA for Grade 3 and higher infection.

Serious pneumocystis jiroveci pneumonia (PJP) infection occurred in 0.6% of 317 patients treated with ALIQOPA monotherapy. Before initiating treatment with ALIQOPA, consider PJP prophylaxis for populations at risk. Withhold ALIQOPA in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis.

Hyperglycemia: Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with ALIQOPA monotherapy. Serious hyperglycemic events occurred in 2.8% of patients. Treatment with ALIQOPA may result in infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours post-infusion and subsequently declined to baseline levels for a majority of patients; blood glucose levels remained elevated in 17.7% of patients one day after ALIQOPA infusion. Of 155 patients with baseline HbA1c <5.7%, 16 (10%) patients had HbA1c >6.5% at the end of treatment.

Of the twenty patients with diabetes mellitus treated in CHRONOS-1, seven developed Grade 4 hyperglycemia and two discontinued treatment. Patients with diabetes mellitus should only be treated with ALIQOPA following adequate glucose control and should be monitored closely.

Achieve optimal blood glucose control before starting each ALIQOPA infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hyperglycemia.

Hypertension: Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with ALIQOPA monotherapy. Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with ALIQOPA may result in infusion-related hypertension. The mean change of systolic and diastolic BP from baseline to 2 hours post-infusion on Cycle 1 Day 1 was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately 2 hours post-infusion; BP remained elevated for 6 to 8 hours after the start of the ALIQOPA infusion. Optimal BP control should be achieved before starting each ALIQOPA infusion. Monitor BP pre- and post-infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hypertension.

Non-infectious Pneumonitis: Non-infectious pneumonitis occurred in 5% of 317 patients treated with ALIQOPA monotherapy. Withhold ALIQOPA and conduct a diagnostic examination of a patient who is experiencing pulmonary symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. Patients with pneumonitis thought to be caused by ALIQOPA have been managed by withholding ALIQOPA and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of non-infectious pneumonitis.

Neutropenia: Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with ALIQOPA monotherapy. Serious neutropenic events occurred in 1.3%. Monitor blood counts at least weekly during treatment with ALIQOPA. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of neutropenia.

Severe Cutaneous Reaction: Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with ALIQOPA monotherapy respectively. Serious cutaneous reaction events were reported in 0.9%. The reported events included dermatitis exfoliative, exfoliative rash, pruritus, and rash (including maculo-papular rash). Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of severe cutaneous reactions.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ALIQOPA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis caused embryo-fetal death and fetal abnormalities in rats at maternal doses as low as 0.75 mg/kg/day (4.5 mg/m2/day body surface area) corresponding to approximately 12% the recommended dose for patients. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least one month after the last dose.

Adverse Drug Reactions: Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most frequently observed adverse drug reactions (≥20%) in ALIQOPA-treated patients were: hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%).

Drug Interactions: Avoid concomitant use with strong CYP3A inducers. Reduce the ALIQOPA dose to 45 mg when concomitantly administered with strong CYP3A inhibitors.

Lactation: Advise women not to breastfeed. Advise a lactating woman not to breastfeed during treatment with ALIQOPA and for at least 1 month after the last dose.

For important risk and use information about Aliqopa, please see the full Prescribing Information.

About CHRONOS-3
CHRONOS-3 is a Phase III randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of Aliqopa in combination with rituximab versus placebo in combination with rituximab in patients with relapsed indolent NHL who have received at least one or more lines of prior rituximab-containing therapy. Histological subtypes included in the trial were follicular lymphoma (FL), small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), and marginal zone lymphoma (MZL). Patients who had a progression-free and treatment-free interval of at least 12 months after completion of the last rituximab-containing regimen or patients unwilling/unfit or for who chemotherapy was contraindicated by reason of age, co-morbidities and/or residual toxicity were included (NCT02367040). The study enrolled 458 participants.2

About non-Hodgkin’s Lymphoma
Non-Hodgkin’s Lymphoma (NHL) comprises a highly heterogeneous group of chronic diseases with poor prognosis. NHL is the most common hematologic malignancy and the eleventh most common cancer worldwide, with nearly 510,000 new cases diagnosed in 2018. It accounted for nearly 249,000 deaths worldwide in 2018.6,7

Indolent NHL consists of multiple subtypes, including follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM). While the disease is typically slowly growing, it can become more aggressive over time. Despite treatment advances, there remains a need for improved treatment options for the relapsed or refractory stage of the disease. After response to initial therapy, response rates and duration of response decline with subsequent lines of therapy, underscoring the need for patients whose disease has already progressed.

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now expands to six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

On April 10, 2021 Mersana Therapeutics, Inc. (NASDAQ:MRSN), a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody-drug conjugates (ADCs) targeting cancers in areas of high unmet medical need, reported preclinical data from XMT-1660, a B7-H4-targeted Dolasynthen antibody-drug conjugate (ADC), and XMT-2056, an Immunosynthen-based STING-agonist ADC at the Virtual 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held from April 10-15th (Press release, Mersana Therapeutics, APR 10, 2021, View Source [SID1234577819]).

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"The ability of Immunosynthen-based ADCs to activate the innate immune system via STING in tumor cells in addition to tumor-resident immune cells in a targeted manner could offer a significant therapeutic advantage over ADCs that modulate other immune activating pathways. These data demonstrate that XMT-2056 is highly differentiated from other innate immune activating approaches and has the anti-tumor activity and tolerability to support continued development of this novel STING-agonist ADC candidate," said Timothy B. Lowinger, Ph.D., Chief Science and Technology Officer of Mersana Therapeutics. "Additionally, we presented data showing that XMT-1660 outperformed other B7-H4 ADCs in vivo. The inversely correlated expression of B7-H4 and PD-L1 in breast tumors suggests an opportunity for a B7-H4 Dolasynthen ADC to address patients poorly served by checkpoint inhibitors. We expect to complete IND-enabling studies and advance both XMT-1660 and XMT-2056 into the clinic in early 2022."

"These encouraging data for both the Dolasynthen and Immunosynthen platforms demonstrate the scientific prowess of the Mersana research team and our commitment to discover and develop life-changing antibody-drug conjugates for patients fighting cancer," said Anna Protopapas, President and Chief Executive Officer of Mersana Therapeutics.

Details of the posters are as follows:

Poster Title: XMT-1660, a B7-H4-targeted Dolasynthen antibody-drug conjugate for the treatment of breast cancer
Poster Number: 907
Session Category: Experimental and Molecular Therapeutics
Session Title: Antibody Technologies

These data show that B7-H4 is a promising target for a Dolasynthen ADC due to its expression and function. B7-H4 is expressed across multiple different tumor types with high unmet medical need, including breast, endometrial and ovarian. XMT-1660 demonstrated robust in vivo activity against multiple triple-negative breast cancer models, as well as an ER+/HER2- breast cancer model, all of which express B7-H4.

In the MX-1 triple-negative breast model, XMT-1660 showed complete, durable regressions of tumors at a DolaLock payload dose of 0.15 mg/kg. In contrast, the DAR-2 and DAR-12 ADCs required twice the payload dose for comparable efficacy. XMT-1660 also showed superior efficacy at matched payload doses in the TNBC patient-derived xenograft model HBCx-24, and in the ER+/HER2- breast cancer PDX model HBCx-19 versus comparators.
Pharmacokinetics of XMT-1660 as well as the Dolasynthen DAR-2 and Dolaflexin DAR-12 comparator ADCs were evaluated in tumor-bearing mice and all were shown to be highly stable in vivo. Pharmacokinetics and tolerability of XMT-1660 and the Dolasynthen DAR-2 ADC were evaluated in non-human primates at equivalent payload doses. The PK and tolerability profiles were comparable and both ADCs exhibited high stability. These results, together with the superior efficacy of XMT-1660, support the selection of XMT-1660 for further development and for clinical study for the treatment of B7-H4-expressing tumors, such as breast, endometrial and ovarian.
Poster Title: XMT-2056, a well-tolerated, Immunosynthen-based STING-agonist antibody-drug conjugate which induces anti-tumor immune activity
Poster Number: 1738
Session Category: Immunology
Session Title: Immunomodulatory Agents and Interventions

These data suggest that XMT-2056, an Immunosynthen STING-agonist ADC, can overcome the limitations of the current therapeutic approaches, enabling tumor-targeted delivery of a STING agonist with improved efficacy and tolerability over a free IV STING agonist. Anti-tumor activity of Immunosynthen STING-agonist ADCs involves targeted activation of the STING pathway in both tumor-resident immune cells and tumor cells, delivering a one-two punch with the potential to increase the therapeutic index.

In vitro studies show that XMT-2056 has potent STING activity with >100-fold improvement in activity in comparison to the free STING-agonist payload.
XMT-2056 shows excellent in vivo efficacy even after a single IV dose, while having minimal effect on systemic cytokines. A single, low dose administration of XMT-2056 led to sustained tumor regressions in mice in comparison to the IV STING agonist which showed modest activity even at a dose approximately 100 times higher than that of the ADC. In contrast, when comparing the effect on systemic cytokine levels, the IV STING agonist had significantly higher levels compared to the STING-agonist ADC, which supports the hypothesis that a STING-agonist ADC can target STING activation to the tumor microenvironment, leading to improved anti-tumor activity and a significantly greater therapeutic index.
In vitro and in vivo studies demonstrate that STING agonist ADCs are able to activate the STING pathway in both tumor-resident immune cells and tumor cells, offering a potential advantage over other innate immune activating pathways.
To evaluate the safety profile, XMT-2056 was administered intravenously to non-human primates (NHP) in single and repeat-dose studies at multiple dose levels. XMT-2056 shows favorable pharmacokinetics in NHPs and is well tolerated at a dose level >10-fold higher than required for sustained tumor regression in mice models. Together these data support the clinical development of XMT-2056.
Poster Title: Tumor cell-intrinsic STING pathway activation leads to robust induction of Type III Interferons and contributes to the anti-tumor activity elicited by STING agonism
Poster Number: 1773
Session Category: Immunology
Session Title: Innate Immunity to Tumors

STING pathway agonism induces anti-tumor immunity by upregulating a Type I interferon response within the tumor microenvironment. While systemically or intra-tumorally administered free STING agonists are currently being evaluated in the clinic, these data suggest that a STING-agonist ADC, in which the STING agonist is conjugated to an antibody directed to a tumor antigen, can overcome the limitations of the current therapeutic approaches.

In vitro studies show that while most cancer cell lines do not respond to STING agonism in standard monoculture conditions, Immunosynthen STING-agonist ADCs do activate STING in the same cancer cells in the presence of immune cell-conditioned media, suggesting that the tumor cell-intrinsic STING pathway can be activated in the presence of cues from immune cells.
Nanostring analysis of human tumor xenografts reveal tumor cell specific induction of type III interferons (IFNs) by tumor cell-targeting Immunosynthen STING-agonist ADCs. In vitro studies confirmed the Type III interferon induction at the mRNA and cytokine level. Type III interferon production was markedly reduced in STING knock out cancer cell and immune cell co-cultures, suggesting that the tumor intrinsic STING activation is required for a robust Type III interferon induction in response to STING agonism. In addition, these data show that blocking Type III IFNs with neutralizing antibodies in cancer cell:immune cell co-cultures inhibits the production of key cytokines and cancer cell killing induced by STING-agonist ADC treatment, pointing to a potentially important role for Type III IFNs in anti-tumor immune responses downstream of STING pathway activation in tumor cells.
Together these data demonstrate that tumor cell intrinsic STING activation leads to a robust type III interferon induction, which contributes to the anti-tumor activity of tumor cell-targeted STING-agonist ADCs. This study supports the further development of Immunosynthen STING-agonist ADC candidates.

On April 10, 2021 Vincerx Pharma, Inc. (Nasdaq: VINC) is a biopharmaceutical company reported that aspiring to address the unmet medical needs of cancer patients through paradigm-shifting therapeutics (Press release, Vincerx Pharma, APR 10, 2021, View Source [SID1234577836]). Today, Vincerx presented preclinical data characterizing VIP236, a novel small molecule drug conjugate (SMDC) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 . The SMDC is comprised of an αvβ3 integrin antagonist linked to a cytotoxic camptothecin (CPT) derivative, designed to selectively release its payload via neutrophil elastase in the tumor microenvironment (TME).

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"These preclinical data demonstrate that VIP236 has enhanced tumor specificity via tumor specific binding through αvβ3 integrin and targeted drug release in the TME with our neutrophil elastase cleavable linker," said Ahmed Hamdy, M.D., Chief Executive Officer of Vincerx. "The payload is a modified camptothecin derivative which has been optimized for high cell permeability and a low efflux ratio. When VIP236 is administered to tumor bearing mice, an over 10-fold higher tumor-to-plasma ratio of the CPT payload was observed, when compared to delivery of the payload alone. Importantly, these properties translate into potent antitumor activity across multiple xenograft models, with tumor regression in all models tested and complete tumor responses in 100% across all dose levels of mice in a triple negative breast cancer model. These compelling data, combined with a favorable tolerability profile, suggest that VIP236 has the potential to provide potent, highly targeted antitumor activity to address the needs of patients with advanced and aggressive cancers. We look forward to continued progress as we advance VIP236 towards the clinic, with first-in-human studies expected in the first half of 2022."

Key Presentation Highlights:

Poster presentation, titled, "A novel small molecule drug conjugate – αvβ3 integrin antagonist linked to a cytotoxic camptothecin derivative – for the treatment of multiple cancer types" presented by Hans-Georg Lerchen, Ph.D., Chief Scientific Officer of Vincerx.

VIP236 is a novel SMDC targeted by an αvβ3 integrin antagonist with a neutrophil elastase cleavable linker linked to a modified CPT payload derived from SN38, a well-known cytotoxic drug and active metabolite of irinotecan.
Efficient anti-tumor targeting and greater cytotoxicity is achieved by multiple mechanisms associated with aggressive tumor cells and its microenvironment.
VIP236 targets αvβ3 integrin which is overexpressed by invasive cancer and stromal cells in the TME such as endothelial cells undergoing neovascularization. Efficient tumor homing with the αvβ3 integrin antagonist is demonstrated by the imaging studies.
Neutrophil elastase (NE) is overexpressed in the invasive TME associated with advanced cancers. The abundance of NE in the TME promotes linker cleavage, release of the active modified CPT payload and enhances VIP236 cytotoxicity.
Drug resistant cancer cells often have greater drug efflux capabilities. The CPT payload is modified to improve cellular permeability and lower cell efflux properties resulting in better cytotoxicity in cancer cells overexpressing drug efflux pumps when compared to SN38.
The combination of these properties results in a 10.8-fold higher tumor-to-plasma ratio of the targeted and modified CPT payload compared to administration of the payload alone.
In vivo, VIP236 demonstrates higher antitumor efficacy in comparison to reference chemotherapy drugs across multiple mouse xenograft models.
Complete tumor responses were observed in 100% of mice across all dose levels in the MX-1 triple negative breast cancer model.
Partial responses were observed in 100% of mice in both the NCI-H69 small cell lung cancer and SW480 colorectal cancer mouse models at a VIP236 dose of 40mg/kg.
Across mouse models, VIP236 showed good tolerability as evidenced by less than 5% mean body weight loss.
The poster can be accessed on the presentations section of the Vincerx website.