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 Pieris Pharmaceuticals, Inc. (NASDAQ:PIRS), a clinical-stage biotechnology company advancing novel biotherapeutics through its proprietary Anticalin technology platform for respiratory diseases, cancer, and other indications, reported a clinical data update from the phase 1 monotherapy study of cinrebafusp alfa (PRS-343), a 4-1BB/HER2 bispecific for the treatment of HER2-expressing solid tumors, in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Congress 2021 (Press release, Pieris Pharmaceuticals, APR 10, 2021, View Source [SID1234577822]). The Company also presented preclinical data for PRS-344/S095012, a 4-1BB/PD-L1 bispecific the Company is developing with Servier, at a poster session at the congress.

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Cinrebafusp Alfa (PRS-343):

Presented data demonstrated additional clinical benefit at the highest dose, including an additional, ongoing confirmed durable partial response, three additional patients with stable disease as best response, and overall durable benefit. Based on clinical benefit and pharmacodynamic correlates, cinrebafusp alfa showed a clear dose response and a 4-1BB-driven mechanism of action. Additionally, clinical benefit was observed in patients with "cold" tumors as well as those with HER2-low expressing tumors. Cinrebafusp alfa continues to be well-tolerated. The Company plans to initiate a phase 2 study in gastric cancer this summer that will evaluate both HER2-high and HER2-low patient settings.

As of the cut-off date of February 25, 2021, 8 patients in the monotherapy trial were evaluable for a response at the highest dose cohort (cohort 13b; 18 mg/kg Q2W) out of a total of 42 response-evaluable patients enrolled in the predicted active dose cohorts (cohort 9 and higher; ≥2.5 mg/kg) in the study.

In cohort 13b, one additional patient (cancer of unknown primary) achieved an ongoing confirmed durable partial response, for an updated overall response rate (ORR) of 25% in that cohort as compared to an ORR of 12% across active dose levels.
In cohort 13b, three additional patients experienced stable disease as best response, for an updated disease control rate (DCR) of 63% in that cohort as compared to a DCR of 52% across active dose levels.
Cinrebafusp alfa activates adaptive and innate immunity in the tumor microenvironment, consistent with intended mode of action as evidenced by post-treatment increases in CD8+ T cells, NK cells and cytotoxic activity.
Dose-dependent increases of CD8+ T cells in the tumor and soluble 4-1BB in the blood of patients demonstrate target engagement and a 4-1BB-driven mode of action.
Cinrebafusp alfa shows preliminary evidence of activity among "cold" tumor types as well as "hot" tumor types.
Activity in HER2-low expressing patients supports continued development of cinrebafusp alfa in that population, which the Company will evaluate in its phase 2 gastric cancer study.
Cinrebafusp alfa monotherapy appeared to be well-tolerated up to 18 mg/kg, with no significant specific anti-HER2 or anti-4-1BB safety signal and no dose limiting toxicity identified.
The cinrebafusp alfa data presented at AACR (Free AACR Whitepaper) can be found in an updated corporate presentation at View Source

PRS-344S095012:

The synergistic preclinical data presented for PRS-344/S095012 demonstrate PRS-344/S095012 is superior to the combination of PD-L1- and 4-1BB-targeting molecules. In an anti-PD-L1-resistant mouse model, the drug candidate induces a dose-dependent anti-tumor response and significantly extends survival. In vitro, PRS-344/S095012 enhances effective CD8+ T cell response and proinflammatory cytokine release.

PRS-344/S095012-mediated 4-1BB activation is strictly PD-L1 dependent, reducing the risk of peripheral toxicity. Furthermore, 4-1BB co-stimulation only occurs in combination with simultaneous TCR signaling, restricting its activity to antigen-specific T cells. PRS-344/S095012 also displays mAb-like pharmacokinetics in mice.

These data support further development of PRS-344/S095012, for which the phase 1 study is expected to begin this year.

A copy of the poster is available at this link.

"The matured data from the highest dose cohort of cinrebafusp alfa demonstrate a clear dose-dependent response that supports our recommended phase 2 dose, and the biomarker data generated across all active dose cohorts demonstrate that cinrebafusp alfa activity is 4-1BB-driven and that the drug candidate is active not only in HER2-high expressing tumors, but also HER2-low expressing tumors – a significant opportunity and unmet medical need that we are excited to pursue in our upcoming phase 2 study," said Stephen S. Yoder, President and Chief Executive Officer of Pieris. "Separately, we are pleased with the clear evidence of dose-dependent synergistic anti-tumor effects of PRS-344/S095012, as well as further evidence for its tumor-localized mechanism of action, and we look forward to moving this asset into the clinic this year. By its design, this bispecific has best-in-class potential in the 4-1BB/PD-L1 arena."

About Cinrebafusp Alfa:

Cinrebafusp alfa (PRS-343) is a 4-1BB/HER2 fusion protein comprising a 4-1BB-targeting Anticalin protein and a HER2-targeting antibody. The drug candidate is currently in development for the treatment of HER2-positive solid tumors. Based on encouraging phase 1 study results, which demonstrated clinical benefit as single agent and biomarker data indicative of a 4-1BB-driven mechanism of action, the Company is actively working towards initiating a phase 2 study of cinrebafusp alfa in combination with ramucirumab and paclitaxel for the treatment of HER2-high expressing gastric cancer and in combination with tucatinib in HER2-low expressing gastric cancer.

On April 10, 2021 Synlogic, Inc. (Nasdaq: SYBX), a clinical stage company bringing the transformative potential of synthetic biology to medicine, reported data on SYNB1891 for the treatment of solid tumors and lymphoma during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, April 10-15, 2021 (Press release, Synlogic, APR 10, 2021, View Source [SID1234577821]).

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The presentation, "Intratumoral injection of SYNB1891, a Synthetic Biotic designed to activate the innate immune system, demonstrates target engagement in humans including intratumoral STING activation," was delivered by Dr. Filip Janku, Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. The presentation recording will be available throughout the duration of the conference.

SYNB1891 is an investigational drug being evaluated in an ongoing Phase 1 clinical trial for the treatment of solid tumors and lymphoma. SYNB1891 is composed of an engineered Synthetic Biotic strain of E. coli Nissle that produces cyclic di-AMP (CDA), a stimulator of the STING (STimulator of INterferon Genes) pathway. This mechanism can play a critical role in the initiation of an anti-tumor immune response via activation of APCs and presentation of tumor antigens. Findings from the monotherapy cohorts include:

SYNB1891 is safe and well-tolerated as an intratumoral injection in a heterogenous population.
No dose limiting toxicities or SYNB1891-related infections
Dose levels through 1e7 live cells demonstrate target engagement as assessed by dose-dependent increases in serum cytokines, upregulation of ISGs and presence of tumor infiltrating lymphocytes.
Evidence of durable stable disease was seen in 2 patients and was associated with upregulation genes tied to immune activation and increased intratumoral lymphocytes.
These data support continued dose escalation in the monotherapy and combination arms. The combination arm of the study combines escalating dose levels of SYNB1891 with a fixed dose of a PD-L1 checkpoint inhibitor antibody to establish a recommended Phase 2 dose for the combination regimen.

Data from both arms will continue to be reported over the course of 2021, with mature combination therapy data expected by the end of the year.

Learn more about Synlogic’s programs and pipeline by visiting View Source

About SYNB1891
SYNB1891 is an investigational drug for the intra-tumoral treatment of solid tumors and lymphoma, composed of an engineered Synthetic Biotic strain of E. coli Nissle that produces cyclic di-AMP (CDA), a stimulator of the STING (STimulator of INterferon Genes) pathway. This mechanism can play a critical role in the initiation of an anti-tumor immune response via activation of APCs and presentation of tumor antigens. The bacterial chassis of SYNB1891 also stimulates the innate immune system by several other mechanisms, including via Toll-like receptors (TLRs), potentially adding to the magnitude of the overall immune response. While SYNB1891 has been engineered with safety features that are designed to prevent its replication unless supplemented with specific nutrients, the bacteria remain active for several days within the injected tumor to stimulate a local immune response. SYNB1891 is being evaluated in a Phase 1 clinical trial (NCT04167137).

On April 10, 2021 Theratechnologies Inc. (Theratechnologies) (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported that new in vivo preclinical data were presented at the 2021 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Theratechnologies, APR 10, 2021, View Source [SID1234577820]). These data demonstrated sustained tumor regression, better anti-tumor activity and tolerability with TH1902 compared to docetaxel alone in all cancer types studied, namely melanoma, pancreatic, ovarian, endometrial, colorectal and triple-negative breast cancers. The anti-tumor effect of TH1902 persisted longer post-treatment than with docetaxel alone. TH1902 is the Company’s lead investigational peptide-drug conjugate (PDC) derived from its SORT1+ Technology.

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"The FDA fast-track designation for TH1902 was supported by the data presented today. This designation is a significant recognition of our SORT1+ Technology as very few investigational therapies receive fast track designation based on preclinical data. It strongly endorses TH1902 as a potentially new and innovative treatment for all patients with sortilin positive (SORT1+) solid tumors that are refractory to standard therapy. The Phase 1 clinical trial is now underway and we look forward to advancing TH1902 through further stages of its development," said Dr. Christian Marsolais, Senior Vice President and Chief Medical Officer, Theratechnologies.

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.