Stockwinners Market Radar for April 11, 2021 - Earnings, Upgrades downgrades, option trades, Best Stock Advisory Service

20:05 EDT Fly Intel: Top five weekend stock stories - Catch up on the weekend's top five stories with this list compiled by The Fly: 1. Microsoft (MSFT) is in advanced talks to buy Nuance Communications (NUAN) in a deal with an equity value of about $16B, or about $56 per share, reported Bloomberg's Liana Baker, Kiel Porter, and Dina Bass, citing people familiar with the matter. Microsoft and Nuance have collaborated since 2019, noted the report, which added that an agreement could be announced as soon as this week. 2. DiaSorin SpA (DSRLF) announced that its Board of Directors has unanimously approved and signed a definitive merger agreement for DiaSorin to acquire Luminex (LMNX) for a price of $37 per share in an all-cash transaction. This corresponds to a total equity value of approximately $1.8B on a fully diluted basis and an enterprise value of approximately $1.8B. Following the acquisition, the combined entity will have combined 2020 revenues of approximately EUR 1.25B, adjusted EBITDA of approximately EUR 472M, and positive Net Financial Position of approximately EUR 335M. The transaction is expected to close within the third quarter of 2021 and is subject to Luminex shareholder approval and to other customary closing conditions, including the satisfaction of antitrust and CFIUS regulatory requirements. The transaction will be immediately accretive to DiaSorin's earnings per share following closing of the transaction and will generate an attractive return on invested capital profile. The combination is also anticipated to result in cost synergies of approximately $55M within 3 years after closing. 3. The next few months should be boom times for retailers as stimulus checks pump up the economy, but consumers aren't shopping the way they used to as they are souring on credit, and they are increasingly likely to shop online with a digital wallet rather than pull out cash in a store, Daren Fonda wrote in this week's edition of Barron's. The trends are fueling the "buy now, pay later," and they could lift the shares of Affirm Holdings (AFRM), added the author. 4. Legendary and AT&T (T) subsidiary Warner Bros.' "Godzilla vs. Kong" stayed number 1 in its second outing with an estimated $13.4M from 3,084 locations for a domestic cume of $69.5M and a global total of about $360M. The movie is expected to pass up "Tenet" at $365M worldwide sometime this week to rank as the top-grossing during this pandemic. 5. II-VI (IIVI) and Goldman Sachs (GS) saw positive mentions in this week's edition of Barron's, while Carnival (CCL), Norwegian Cruise Line Holdings (NCLH), Royal Caribbean Group (RCL), and Credit Suisse (CS) were mentioned cautiously.

18:24 EDT Checkmate presents new clinical trial translational data with Vidutolimod - Checkmate Pharmaceuticals announced the presentation of new translational data from Checkmate's Phase 1b trial of vidutolimod in combination with pembrolizumab in patients with advanced anti-PD-1 refractory melanoma. Key highlights from these clinical data include: 93% of patients had progressive disease as their last response assessment on prior PD-1 blockade therapy, 42% had an elevated LDH, and the median sum of the target lesions longest diameter was 6.7 cm, indicating advanced disease; Response rates to vidutolimod in combination with pembrolizumab were similar across baseline patient characteristics including BRAF mutation, LDH level, number of prior systemic cancer treatments, best response to prior PD-1 blockade therapy, and prior ipilimumab; Responders and non-responders were not distinguished by baseline tumor characteristics including PD-L1 CPS, IFNg transcriptional signature, CD8+ T cells, or nonsynonymous mutations; All patients showed the expected rapid induction of anti-Qb antibodies to the virus-like particle, which facilitate the pharmacodynamic response to vidutolimod, and the antibody titers were not associated with clinical response; Clinical activity of vidutolimod in combination with pembrolizumab was associated with serum CXCL10 induction magnitude, induction of an inflammatory gene expression profile, and CD8+ T cells in injected and noninjected tumors.

18:14 EDT Lyra Therapeutics presents full data set from LANTERN Phase 2 study - Lyra Therapeutics presented data from its Phase 2 LANTERN study of LYR-210, the company's lead long-acting product candidate for chronic rhinosinusitis, at the Combined Otolaryngology Spring Meetings 2021. LYR-210 is an investigational product candidate designed to be administered in-office and to deliver a sustained release therapeutic for up to six months at difficult-to-access nasal inflammation sites, as a non-invasive alternative to surgery for patients who have failed medical management. Lyra reported positive topline data from the LANTERN study in December 2020. The COSM oral presentation, titled Long-acting implantable corticosteroid matrix for chronic rhinosinusitis: Results of LANTERN Phase 2 randomized controlled study, contains the full 24-week data set from the company's Phase 2 clinical trial of LYR-210. Previously unpublished data included: improvement from baseline in bilateral ethmoid Zinreich scores by magnetic resonance imaging; symptom improvement in both polyp and non-polyp patients; and the need for and use of rescue medication during the trial. In Polyp vs Non-Polyp patients, symptom improvement was observed in both polyp and non-polyp patients, with 100% of patients at the 7500microgram dose in each group achieving the minimal clinically important difference of 8.9 points for SNOT-22 total score by week 24, with a single administration of LYR-210. In the LANTERN study, subjects underwent paranasal sinus MRI at baseline as well as at the end of treatment. LYR-210 achieved improvement in bilateral ethmoid Zinreich scores at week 24 in a dose-dependent manner, providing evidence of disease modification, with the 7500microgram dose achieving significant improvement compared to control between the two timepoints. Only 1 patient in the 7500microgram group and 2 patients in the 2500microgram group required a rescue treatment compared to 7 patients in the control group over the 24-week treatment period. The first incidence of rescue treatment in the control group occurred at week 2, while the only patient to require rescue treatment in the 7500microgram group did not require rescue treatment until after week 18. As such, LYR-210 reduced the need for rescue treatment. The need for rescue treatment in the LANTERN study was determined by the treating physician. Separately, Lyra has shared an analysis of the LANTERN study focused on a composite of three of the cardinal symptoms of CRS. Lyra announced an analysis of a composite score of three cardinal symptoms of CRS, which includes nasal blockage, nasal discharge and facial pain, which are the most prevalent symptoms for surgically naive CRS patients both with and without nasal polyps. With a single administration, LYR-210 achieved statistically significant improvement in the 3CS composite score compared to control at week 24 and at earlier timepoints.

18:05 EDT Eli Lilly presents new data on Retevmo in Advanced RET Fusion-Positive in GI - Eli Lilly announced for the first time data from the Phase 1/2 LIBRETTO-001 trial showing treatment with Retevmo demonstrated encouraging antitumor activity and safety across RET fusion-positive advanced solid tumors beyond lung and thyroid cancers, including multiple treatment-refractory gastrointestinal malignancies. In the Phase 1/2 LIBRETTO-001 trial, 32 adult patients with 12 unique RET fusion-positive advanced cancer types were enrolled by the efficacy cutoff date of September 19, 2020. Cancer types treated included pancreatic, colon, breast, salivary, sarcoma, carcinoid, rectal neuroendocrine, small intestine, xanthogranuloma, ovarian, pulmonary carcinosarcoma, and unknown primary cancers. Among the 32 patients, 62.5 percent had gastrointestinal tumors. Across all 32 patients, the confirmed objective response rate was 47 percent. Confirmed responses were observed in nine unique RET fusion-positive advanced cancer types. The median duration of response was not reached, with median follow-up of 13 months. Responses were ongoing in 73 percent of responding patients.

17:59 EDT Greenwich LifeSciences presents immune response Phase IIb Poster - Greenwich LifeSciences presented a poster of the final 5 year GP2 Phase IIb clinical trial immune response data at the 2021 AACR Annual Meeting. 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. The company said that 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 with GP2 immunotherapy in combination with trastuzumab 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.

17:55 EDT Mirati presents preclinical data on novel approach to PRMT5 inhibition - Mirati Therapeutics announced initial preclinical results evaluating its investigational synthetic lethal PRMT5 inhibitor in methylthioadenosine phosphorylase-deleted cancer models. Mirati's internally discovered PRMT5 compound is the first to specifically target the PRMT5/methylthioadenosine complex. This approach is designed to leverage elevated levels of MTA in cancers exhibiting an MTAP deletion and to selectively kill cancer cells harboring this genetic alteration. Preclinical results showed that the Mirati PRMT5 compound bound selectively to the PRMT5/MTA complex and demonstrated a greater than 100-fold selectivity for MTAP-deleted cells compared with cells that do not exhibit this genetic defect in both proliferation and mechanistic assays. This selectivity for the PRMT5/MTA complex and MTAP-deleted cancer cells allows for the selective targeting of cancer cells while sparing healthy cells, which are also dependent on PRMT5 for cell growth and survival. In addition, treatment of MTAP-deleted tumor xenograft-bearing mice with the Mirati PRMT5 compound resulted in halted tumor growth and near complete reduction of symmetric dimethylarginine, a biomarker of PRMT5 activity, at well-tolerated dose levels.

17:50 EDT OncoCyte presents new data on potential for pan-cancer utility of DetermaIO - Oncocyte Corporation presented new data at the American Association for Cancer Research Annual Meeting 2021. The presentations featured studies of Oncocyte's novel predictor of immunotherapy response, DetermaIO, demonstrating test performance in bladder cancer, now the third cancer type, suggesting potential applicability across multiple cancer types. DetermaIO has previously been shown to predict immunotherapy response in lung and breast cancers in studies using four different approved checkpoint inhibitors - Keytruda, Opdivo, Tecentriq and Imfinzi. At the conference, Oncocyte debuted data in bladder cancer in two studies, including one highlighted in a podium presentation. The poster, titled "Pathway modeling to translate the 27-gene immuno-oncology algorithm into bladder cancer," detailed the application of the DetermaIO test and proprietary algorithm for the classification of metastatic bladder cancer. This study demonstrated a novel approach of looking at the tumor microenvironment at a genomic scale, as well as validating the use of the test, without any further modification, in bladder cancer to assess its association with Immune Checkpoint Inhibitor response. During the podium presentation, titled "Validation of a 27-gene immuno-oncology algorithm in metastatic urothelial carcinoma treated with an immune checkpoint inhibitor," the results of a prospectively defined analysis of clinical trial results from the IMvigor210 study of atezolizumab, an immunotherapy used to treat bladder and other cancers, was revealed. Oncocyte's DetermaIO test measures the expression of 27 genes and combines them with a proprietary algorithm to classify the entire tumor immune microenvironment present in solid tumor biopsy samples. The company's previously released data demonstrated that the combination of measuring the "hot" inflammatory immune response combined with the "cold" immune repressive signature coming from the wound response in tumor specimens, is strongly associated with response to ICIs in lung and breast cancer.

17:44 EDT Zentalis announces initial data on ZN-c3 in patients with advanced solid tumors - Zentalis Pharmaceuticals announced initial efficacy and safety data from the Phase 1 dose-escalation portion of its ongoing Phase 1/2 clinical trial of ZN-c3 in patients with advanced solid tumors who are refractory to or ineligible for standard therapy or for whom no standard therapy is available. Initial results showed that monotherapy ZN-c3 use resulted in "Exceptional Responses in heavily pre-treated patients in a range of solid tumors," including Partial Responses in ovarian cancer, colorectal cancer, non-small cell lung carcinoma and uterine serous carcinoma, said the company. In the Phase 1 dose-escalation trial, ZN-c3 was dosed starting at 25 mg and going as high as 450 mg QD in patients with advanced or metastatic solid tumors. At the time of the data cutoff on February 12, 2021, 55 patients were evaluated for safety, the primary endpoint. The study remains ongoing and based on the data presented at AACR, ZN-c3 generated 5 Partial Responses. Best Overall Responses: Two confirmed PRs in ovarian cancer and colorectal cancer patients; After receiving 18 prior lines of therapy, 11 prior lines in the advanced metastatic setting, a patient with Stage IV ovarian cancer had a RECIST-confirmed PR with a 56% reduction in overall target lesions. The patient also experienced a large rapid drop in CA-125 from 610 kU/L at baseline to 125 kU/L within 4 weeks on treatment, with her CA-125 level normalizing 3 weeks later. The patient was on study for 186 days and remains on study drug. After receiving 5 prior lines of therapy in the advanced metastatic setting, a patient with Stage IV CRC had a RECIST-confirmed PR with a 42% reduction in overall target lesions, as well as a rapid decrease in CEA tumor marker from 327 ng/mL at baseline to less than50 ng/mL after 3 weeks on treatment. The patient remained on study for 169 days until clinical disease progression. In addition, three unconfirmed PRs-one in non-small cell lung carcinoma and two in uterine serous carcinoma patients. After receiving 3 prior lines of therapy in the advanced metastatic setting, a patient with Stage IV NSCLC had an unconfirmed PR with a 50% reduction in overall target lesions. The patient was on study for 145 days and remains on study drug. ZN-c3 was generally well-tolerated as a single agent. Significant hematological adverse events were limited. Results from this study indicate that an oral dose of 300 mg QD with continuous dosing is the recommended Phase 2 dose of ZN-c3 when used as a monotherapy. The 300 mg QD dose demonstrated high plasma exposure levels, while minimizing adverse events. In addition, the pharmacodynamic marker of pCDK1 levels in skin punch biopsies showed active target engagement at relevant pharmacological doses. The company initiated the Phase 1 expansion portion of the trial with the 300 mg QD dose earlier in 2021 and is exploring this candidate's potential in combination trials including in ovarian cancer and osteosarcoma. Using this recommended dose, Zentalis will also coordinate with Zentera Therapeutics, Zentalis' majority-owned joint venture, to initiate a Phase 1b trial investigating ZN-c3 as a single agent in China.

17:39 EDT Gracell reports long-term follow-up data on TruUCAR-enabled GC027 - Gracell Biotechnologies presented updated long-term follow-up data on their TruUCAR-enabled allogeneic product candidate GC027 for the treatment of adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia in an e-poster presentation at the 2021 American Association for Cancer Research Annual Meeting. TruUCAR-enabled GC027 is a first-in-human, off-the-shelf allogeneic CAR-T stand-alone therapy targeting CD7. An ongoing, multi-center investigator-initiated Phase 1 trial in China is evaluating the safety and efficacy of GC027 for the treatment of adults with r/r T-ALL. The updated data with a February 4, 2021 data cut-off represents long-term follow-up as well as additional patients treated. Patients had received a median of six prior lines of therapy and received a single infusion of TruUCAR GC027 in one of three dose levels: 0.6x107cells/kg, 1.0x107cells/kg or 1.5x107cells/kg. Six patients treated achieved a complete remission with or without complete blood count recovery and five of the six patients achieved minimum residual disease negative complete remission. At 6 months post treatment, three out of five patients had maintained MRD- CR. After 18.5 months of follow up for the initial patients treated, one patient continued to be MRD- CR at 16.8 months. One patient maintained MRD- CR until 9 months and one patient with primary refractory disease maintained his MRD- CR status until month 7. One additional patient treated presented initially with a high tumor burden and extensive extramedullary disease. After treatment with GC027 and as confirmed by PET CT scan, all EM lesions resolved. The patient achieved MRD- CR at day 28. All six patients tolerated a single infusion of TruUCAR GC027. No neurotoxicity events or acute graft-versus-host disease were observed. Cytokine release syndrome occurred in all patients and was managed with standard of care including Tocilizumab. Overall safety findings were consistent with previous observations.

17:35 EDT Mersana Therapeutics presents preclinical data on potential of XMT-2056/XMT-1660 - Mersana Therapeutics presented preclinical data from XMT-1660, a B7-H4-targeted Dolasynthen antibody-drug conjugate, and XMT-2056, an Immunosynthen-based STING-agonist ADC at the Virtual 2021 American Association for Cancer Research Annual Meeting. The 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. The second poster presentation shows that 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 greater than100-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 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 greater than10-fold higher than required for sustained tumor regression in mice models. Together these data support the clinical development of XMT-2056. According to poster titled "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," 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 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. The company believes that 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.

17:28 EDT GlycoMimetics presents findings from Phase 1b trial of GMI-1359 - GlycoMimetics announces that a Phase 1b trial of GMI-1359, being conducted at Duke University Cancer Center, showed evidence of on-target effects, immune-activation and cell mobilization in the initial two patients treated with the company's dual antagonist of E-selectin and CXCR4. GMI-1359 is GlycoMimetics' novel small molecule drug candidate, a dual antagonist of E-selectin and CXCR4, designed to target tumor-microenvironment resistance to chemotherapy in cancers with bone metastases. The initial data from the study confirmed the dual CXCR4 and E-selectin antagonist's on-target effects. In the two patients who completed treatment, evaluations of peripheral blood showed a consistent mobilization of CD34+ hematopoietic stem and progenitor cells at doses beginning at 5 mg/kg and a reduction of plasma levels of soluble E-selectin. Furthermore, in one individual, following the administration of 7.0 mg/kg of GMI-1359, an immunophenotyping assessment of peripheral blood showed a redistribution of myeloid derived suppressor cells as evidenced by increased percentages of both the monocytic and granulocytic MDSCs. In this same individual following administration of 7.0 mg/kg GMI-1359, the incidence of M1 proinflammatory macrophages increased while the M2 anti-inflammatory macrophages, often associated with tumor progression, decreased. The clinical poster concludes that GMI-1359 demonstrated an acceptable safety and tolerability profile in the patients treated to date. No dose limiting toxicities were observed following multiple dose administration up to 7 mg/kg.

17:23 EDT Agenus presents new clinical data on AGEN1181 at AACR Meeting - Agenus presented new clinical data on AGEN1181, its next-generation anti-CTLA-4 antibody, at the American Association for Cancer Research Annual Meeting. In two separate presentations at AACR, Agenus showcased the optimal performance of AGEN1181 in relevant models. In addition, as the clinical data matures, additional responses as well as a conversion from a partial response to a complete response, have been observed. The new data announced include: New partial response in the first melanoma patient treated; New conversion to complete response in ovarian cancer patient; Partial response in microsatellite stable colorectal cancer patient; Partial response in PD-L1(-) ovarian cancer patient; Partial response in MSS colorectal cancer patient; Complete response in PD-L1(-) MSS endometrial cancer patient; Complete response by PET in PD-L1(-) MSS endometrial cancer patient.

17:19 EDT Arcus Biosciences presents updated data for Etrumadenant - Arcus Biosciences presented progression-free survival and overall survival data in patients with advanced metastatic colorectal cancer from the ARC-3 study at the 2021 American Association for Cancer Research Annual Meeting. ARC-3 was a Phase 1/1b, multicenter, open-label, dose-escalation and dose-expansion study that evaluated the safety, tolerability, PK and early clinical activity of etrumadenant, the first dual adenosine A2a/A2b receptor antagonist in the clinic, in subjects with mCRC. Additionally, Arcus presented details of its Hypoxia-Inducible Factor 2alpha research program, including the design of a novel series of HIF-2alpha inhibitors, which has resulted in the identification of molecules such as AB521, with excellent potency, selectivity, biological activity and pharmacokinetic properties suitable for further development. Initial results from ARC-3 demonstrated that etrumadenant + modified FOLFOX-6 in patients with mCRC was well tolerated and associated with a substantial disease control rate across all lines of therapy, including in patients with microsatellite stable disease and RAS/BRAF-mutated mCRC.

17:14 EDT Hookipa announces preliminary Phase 1 immunogenicity data for HB-201, HB-202 - HOOKIPA Pharma announced preliminary Phase 1 immunogenicity data for its lead oncology candidates, HB-201 and HB-202, to treat Human Papillomavirus 16-positive cancers. The results are from an ongoing Phase 1/2 study currently investigating HB-201 as a single-vector therapy and HB-201 and HB-202 as an alternating two-vector therapy for the treatment of advanced metastatic HPV16+ cancers. Preliminary data showed a strong antigen-specific T cell response after one dose of HB-201 or HB-202, based on direct Enzyme-Linked ImmunoSpot T cell analysis. All 5 patients who received a single dose of HB-201 or HB-202 had a strong induction of T cells specific to HPV16+ cancer 2 weeks after administration. An up to 250-fold increase in antigen-specific T cells was observed 2 weeks after a single dose of HB-201 in 4 patients. One patient who received a single dose of HB-202 showed a 150-fold increase in antigen-specific T cells 2 weeks after administration. Importantly, the results are based on direct ELISpot without ex vivo expansion of T cells, underscoring the magnitude of T cell response generated by one dose of HB-201 or HB-202. The data are derived from dose level 2 of ongoing dose escalation, and the recommended Phase 2 doses for HB-201 and HB-202 have not been reached. In addition, analysis of the antigen-specific T cell response showed an increase in CD8+ T cells specific to HPV16+ cancer after a single dose of HB-201 and HB-202. These data were assessed using intracellular cytokine staining followed by flow cytometry, which differentiates antigen-specific CD8+ T cells from antigen-specific CD4+ T cells. Of note, the HPV16+ cancer patients included in this analysis had negligible levels of antigen-specific CD8+ T cells prior to treatment with HB-201 or HB-202. Other preliminary immunogenicity data highlight immune system activation following a single dose of HB-201. Blood samples from 12 patients were assessed across 13 timepoints for levels of 30 different cytokines and chemokines, which play critical roles in activating an immune response. At the time of data cut-off, baseline and day 4 samples were available for 9 of the 12 patients. The analysis showed that, 4 days after a single dose of HB-201, interferon-gamma levels increased in 90% of patients, and an increase in other immune stimulatory cytokines and chemokines was observed. These data comprise an early sign of natural killer cell and/or T cell activation by HB-201. The company believes these preliminary immunogenicity data reinforce the promising anti-tumor activity reported from this trial in December 2020 and are consistent with recently published preclinical data, which showed that intravenous HB-201 administration induced single digit percentage of antigen-specific CD8+ T cells, while alternating administration of HB-201 and HB-202 induced a potent CD8+ T cell response, exceeding 50% of the circulating T cell pool. As the HB-201/HB-202 clinical trial is ongoing, HOOKIPA expects to present additional translational and clinical data at upcoming medical conferences in 2021. The company anticipates these data to further inform the HPV program, as well as other earlier stage programs in its oncology pipeline, including therapeutics for prostate cancer, as it seeks to deliver transformational therapies through induction of antigen-specific CD8+ T cells.

17:06 EDT Advaxis presents translational biomarker data from ADXS-503 Phase 1/2 trial - Advaxis announced 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 Annual Meeting 2021. 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. A novel multi-color flow cytometry analysis was developed to accurately identify PD-1 expression on peripheral blood mononuclear cells 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, have been completed. Part B with ADXS-503 in combination with KEYTRUDA is currently enrolling its efficacy expansion for up to 15 patients at dose level 1 with the potential to proceed to dose level 2 at a later date. Part C, which is evaluating ADXS-503 in combination with KEYTRUDA as a first line treatment for patients with NSCLC with PD-L1 expression greater than or equal to 1% or who are unfit for chemotherapy is currently enrolling patients.

16:59 EDT TCR2 Therapeutics highlights gavo-cel translational data at AACR Annual Meeting - TCR2 Therapeutics announced that clinical and translational data from the dose escalation portion of the company's Phase 1/2 clinical trial of gavo-cel in patients with treatment refractory mesothelin-expressing solid tumors was presented at the American Association for Cancer Research Virtual Annual Meeting. In addition, the company said that preclinical data from its autologous CD70 and allogeneic mesothelin TRuC-T cells would be highlighted in e-posters in the Adoptive Cell Therapy session at AACR. The data reported in gavo-cel poster presentation were from 8 treatment refractory mesothelin-expressing solid tumor patients, 7 mesothelioma and 1 ovarian, that received a single gavo-cel intravenous infusion at 5x107 cells/m2 or 1x108 cells/m2 either alone or following lymphodepletion with fludarabine and cyclophosphamide.

16:53 EDT Blueprint presents preclinical data on broad precision therapy research pipeline - Blueprint Medicines announced data from multiple poster presentations highlighting the breadth of the company's precision therapy pipeline at the virtual American Association for Cancer Research Annual Meeting 2021. Collectively, the presentations, including foundational preclinical data for multiple programs, demonstrate the productivity of the company's scientific platform.

16:47 EDT MEI Pharma reports preclinical data on Voruciclib ability to regulate MYC - MEI Pharma announced preclinical data demonstrating that voruciclib, an orally administered cyclin-dependent kinase inhibitor that is potent against CDK9, has single agent activity against multiple KRAS mutant cancer cell lines and synergistically inhibits growth of KRAS mutant cancers in combination with KRAS inhibitors. Voruciclib is currently in a Phase 1b clinical trial as a monotherapy in patients with relapsed and/or refractory B-cell malignancies and acute myeloid leukemia. The data reported in preclinical models demonstrates that voruciclib: Results in a rapid decrease in the phosphorylation of proteins that promote MYC transcription; Rapidly decreases phosphorylation of MYC protein on Ser62, a site implicated in stabilizing MYC in KRAS mutant cancers; Possesses single agent activity against multiple KRAS mutant cancer cell lines both in vitro and in vivo; Synergistically inhibits KRAS G12C mutant cancer cell lines in combination with KRAS G12C inhibitors, both in vitro and in vivo.

16:39 EDT Cardiff presents findings from EAP of onvansertib in KRAS-mutated mCRC - Cardiff Oncology announced observations from its Expanded Access Program of onvansertib in KRAS-mutated metastatic colorectal cancer, featured in a virtual oral poster presentation at the American Association for Cancer Research Annual Meeting 2021. The company's investigational drug, onvansertib, a first-in-class, third-generation Polo-like Kinase 1 inhibitor, is being evaluated in combination with standard-of-care chemotherapy and targeted therapeutics. Cardiff Oncology's EAP has enrolled participants who failed or progressed on multiple lines of standard-of-care treatment and uses the same combination regimen and dosing schedule as the company's ongoing Phase 1b/2 mCRC clinical trial. The median progression free survival of evaluable participants in the EAP is 5.6 months to-date, which represents an increase over the 2-3 months mPFS of historical controls1. 62.5% of participants had a greater than 50% decrease in KRAS MAF after one cycle of treatment and continue to show a durable response, having not yet reached the mPFS. Onvansertib has been well tolerated with no serious adverse events reported as of the AACR cutoff date.

16:25 EDT iTeos announces preliminary data from ongoing Phase 1/2a trial of EOS-448 - iTeos Therapeutics announced a presentation featuring preliminary clinical data from 22 adult patients in the ongoing Phase 1/2a trial of its anti-TIGIT antibody, EOS-448, at the American Association of Cancer Research Annual Meeting 2021. The presentation highlights initial findings from the completed dose escalation monotherapy portion of the trial, indicating a favorable tolerability profile and early signs of clinical activity in advanced cancers. The objective of the dose escalation portion of the ongoing EOS-448 trial, presented at AACR, is to evaluate primary objectives of safety and tolerability, and secondary objectives of pharmacokinetics, pharmacodynamics, and antitumor activity of EOS-448 as a monotherapy in patients with advanced solid tumor cancers. As of the data cut-off, the trial had enrolled 22 advanced cancer patients with solid tumors for whom no standard treatment was available. The patients received EOS-448 intravenously once every two weeks or once every four weeks according to their dose and schedule allocation. Doses of 20, 70, 200, 700 mg Q2W and 1400 mg Q4W were evaluated. Since the data cut-off for the AACR poster, as of March 9, 2021, an additional 11 patients have received single agent EOS-448. In addition to the five dose levels which were described at AACR, patients have also received doses of 400mg Q4w and 700mg Q4w. EOS-448 was generally well-tolerated at all tested doses in patients with advanced cancer. Preliminary evidence of clinical activity as a monotherapy, including a confirmed partial response in one pembrolizumab-refractory melanoma patient and disease stabilization in nine patients, was also observed. The most common treatment related adverse events were itching, infusion-related reactions, fatigue, rash and fever, and one treatment related serious adverse event, a grade 2 systemic inflammatory response, was observed. As of March 9, 2020, two additional treatment-related serious events have been reported: Grade 2 Systemic Inflammatory Response and Grade 3 infusion-related reaction. PK assessments indicated a linear and dose-proportional response and PD assessments showed complete target engagement. Biomarker analyses showed evidence of FcgammaR engagement, as demonstrated by a reduction in suppressive immune cells and immune cells considered to be exhausted in the blood, including TIGIT+ regulatory T cells and TIGIT+ CD8 T cells, with only a slight reduction in the total CD8+ T cell count. A shift towards a more functional immune response was observed, with a two-fold increase in the ratio of CD8+ T cells to Treg and a four-fold increase in the ratio of CD8+ TIGIT- T cells to CD8+ TIGIT+ T cells.

16:06 EDT Black Diamond Therapeutics announces preclinical data on BDTX-189, BDTX-1535 - Black Diamond Therapeutics announced the presentation of preclinical data on BDTX-189 and BDTX-1535 at the American Association for Cancer Research Annual Meeting. Preclinical PK BDTX-189 Data includes: Black Diamond employed a novel physiologically based pharmacokinetic (PBPK) modeling strategy, accounting for compound-specific determinants of BDTX-189 metabolism and disposition, to prospectively predict the clinical PK profile and active dose range of BDTX-189; Preclinical PBPK modeling indicated that BDTX-189 would be readily orally absorbed with a short elimination half-life while maintaining suppression of ErbB pathway biomarkers over the dosing interval, consistent with the irreversible mechanism of action and the desired PK/PD profile; Active dose levels in humans were projected to be in the 400-800 mg QD range based on the exposure-tumor growth inhibition relationship in multiple mouse patient-derived xenograft models harboring ErbB allosteric mutations; Enrollment and dosing of patients in the Phase 1/2 MasterKey-01 study of BDTX-189 is ongoing, and the Company is on track to complete the dose-escalation portion of the Phase 1 clinical trial in the first half of 2021. Preclinical BDTX-1535 Data includes: GBM tumors express a family of allosteric oncogenic EGFR variants that often appear together in GBM and, as shown by the Company's preclinical work, must all be effectively inhibited to secure a meaningful anti-tumor response. In cell-based assays, BDTX-1535 achieved potent and selective inhibition of all members of the family of oncogenic EGFR variants expressed in GBM; BDTX-1535 demonstrated a favorable brain-penetrant PK profile in mouse, rat, and dog models; Tumor growth inhibition in mouse models bearing intracranial GBM6 patient-derived tumors expressing allosteric EGFR mutants was achieved. BDTX-1535 demonstrated potent and selective inhibition of rare Exon 18 mutations and the C797S mutation, supporting the potential for utility beyond GBM, such as in NSCLC. Black Diamond expects to file an Investigational New Drug application for BDTX-1535 in the first half of 2022.

16:01 EDT Kymera presents data on dual-targeting activity of IRAKIMiD Degrader KT-413 - Kymera Therapeutics presented late-breaking preclinical data showing how the dual targeting of IRAK4 and IMiD substrates by KT-413, its IRAKIMiD degrader currently in preclinical development, synergizes to impact signaling and cell killing in MYD88-mutant diffuse large B cell lymphoma in a manner that is distinct from IMiDs or selective IRAK4 targeting alone. IRAKIMiDs are novel heterobifunctional degraders designed to degrade both IRAK4 and IMiD substrates, including Ikaros and Aiolos, with a single small molecule. IRAKIMiDs synergistically target both the MYD88-NFkB and IRF4-Type 1 interferon pathways to enhance and broaden anti-tumor activity in MYD88-mutant DLBCL. KT-413 is being developed initially for the treatment of relapsed/refractory MYD88-mutant DLBCL, with the potential to expand into other MYD88-mutant indications and IL-1R/NFkB-driven malignancies. KT-413 is currently in preclinical development and Kymera plans to submit an Investigational New Drug Application to the U.S. Food and Drug Administration and, if cleared, initiate a Phase 1 clinical trial in relapsed/refractory B cell lymphomas, including MYD88-mutant DLBCL, in the second half of 2021. Data highlights include: KT-413 showed superior cell killing compared to the potent IMiD CC-220 or the IRAK4-selective degrader KTX-545 across MYD88-mutant DLBCL cell lines; In an in vivo MYD88-mutant mouse xenograft model, intermittent dosing of KT-413 induced deep and sustained tumor regressions, whereas the IMiDs pomalidomide or CC-220 showed only tumor stasis or slight regressions; KT-413 uniquely inhibited both IRAK4-dependent MYD88-NFkB signaling and IMiD substrate-dependent IRF4 upregulation and Type 1 interferon response suppression, whereas CC-220 and KTX-545 affected only IRF4-Type 1 interferon or MYD88-NFkB signaling, respectively; Global transcriptomics analysis showed KT-413 induced significantly greater downregulation of NFkB, cell cycle and DNA replication pathways, as well as greater activation of interferon and apoptosis pathway signaling, compared to CC-220 or KTX-545.

15:57 EDT Genocea presents novel preclinical Inhibigen data at AACR Annual Meeting - Genocea Biosciences presented preclinical data that offers new insights into Inhibigen-associated responses and continues to underscore the detrimental impact of their inclusion in cancer immunotherapies at the American Association for Cancer Research Annual Meeting 2021. The findings - powered by Genocea's proprietary ATLAS platform - "further validate" previous research presented at SITC 2020 and published in Cancer Discovery, together revealing that the presence of an Inhibigen in an otherwise protective immunotherapy can completely reverse the therapy's intended anti-tumor responses, said the company. The new data show that therapeutic vaccination of tumor-bearing mice with a single Inhibigen caused their tumors to hyperprogress, in contrast to a vaccine containing stimulatory antigens that protected them against tumor growth. The combination of this single Inhibigen with the otherwise-protective vaccine abrogated vaccine efficacy and returned tumor growth to levels of unvaccinated mice. The Inhibigen-associated effects included dampening of T cell immune responses as early as four days after a single dose, and a reversal of the infiltration of both lymphoid and myeloid populations into the tumor microenvironment. These data suggest that Inhibigen-specific responses not only dampen systemic immunity, but also revert tumor microenvironments to an immune-cold state - a feature of early-stage tumor growth. Genocea previously demonstrated that Inhibigen vaccination could stifle immune responses to other antigens co-formulated in a vaccine, and that the effect could not be reversed through combination therapy with immune checkpoint inhibitors. Moreover, early data from ATLAS profiling of T cell responses in patients with cancer showed that the relative proportion of Inhibigen- and neoantigen-specific responses prior to treatment appeared to predict clinical efficacy of subsequent ICI therapy.

15:52 EDT NuCana announces five poster presentations at AACR Annual Meeting - NuCana announced the presentation of five posters at the American Association for Cancer Research Annual Meeting 2021 being held virtually April 9 to 14, 2021. Data from all three of NuCana's ProTides in clinical development were presented. NuCana presented two posters on NUC-3373, its ProTide transformation of the active anti-cancer metabolite of 5-fluorouracil, a widely used anti-cancer drug. NUC-3373 has been designed to overcome the main challenges associated with 5-FU and capecitabine, including cancer-resistance mechanisms, the generation of toxic metabolites and unfavorable pharmacokinetic profile. Poster NUC-3373 describes "further encouraging" interim data from 38 patients with metastatic colorectal cancer, said the company. In this difficult-to-treat group, who had received a median of four prior lines of therapy, NUC-3373, with or without leucovorin, demonstrated a 62% disease control rate in the efficacy-evaluable population. Three patients experienced reductions in their target lesions of 40%, 28% and 15% and several patients achieved a longer progression-free survival on NUC-3373 than they had on their prior therapy. NUC-3373 also continues to demonstrate a favorable safety profile with no FBAL or FUTP-associated Grade 3 or 4 toxicities, such as hand-foot syndrome, GI or hematological adverse events. The second NUC-3373 poster showed that NUC-3373-treated colon cancer cells are able to activate a natural killer cell response. NUC-3373 was shown to induce the release of damage associated molecular patterns which may restore NK cell-mediated immune responses by reducing inhibitory signals. Thus, NUC-3373 has the potential to evoke immunogenic cell death and may enhance the clinical utility of immunotherapy agents. NuCana presented two posters on NUC-7738, a ProTide transformation of a novel nucleoside analog, 3'-deoxyadenosine or 3'-dA. NUC-7738, which has several potential anti-cancer mechanisms of action, is being evaluated in a Phase I study in patients with advanced solid tumors who have exhausted all standard therapies. The first poster describes additional interim data from the ongoing Phase I study. These data demonstrate NUC-7738's encouraging anti-cancer activity and favorable tolerability profile. Three case studies were described detailing patients who achieved tumor reductions and prolonged stable disease on NUC-7738. The second poster describes how NUC-7738 was designed to overcome the key cancer resistance mechanisms which have prevented the clinical development of 3'-dA. NUC-7738 was shown to efficiently generate high and prolonged intracellular levels of the active anti-cancer metabolite, 3'-dATP, and to cause cell death by activation of apoptotic pathways, as well as through inhibition of NFkB nuclear translocation. NuCana presented a poster that further demonstrated Acelarin's activity in biliary tract cancer cells. Specifically, the poster described how Acelarin is converted to the active anti-cancer metabolite and demonstrated that it is incorporated into DNA, inducing persistent double-strand breaks. This leads to cell cycle arrest and DNA damage resulting in apoptosis in biliary tract cancer cells.

15:47 EDT Codiak presents data demonstrating potential of Engineered Exosomes - Codiak BioSciences reported new preclinical evidence from Codiak's exoASO-STAT6 program and clinical results from the healthy volunteer portion of the ongoing Phase 1 trial of Codiak's exoIL-12 program at the virtual American Association for Cancer Research Annual Meeting 2021. "These data illustrate the potential of engineered exosomes to target previously undruggable but well-validated pathways in cancer immunotherapy and generate potent single-agent activity," said the company. Both exoASO-STAT6 and exoIL-12 were developed via Codiak's proprietary engEx Platform, which enables the company to engineer exosomes - naturally occurring, extracellular vesicles - with distinct properties, load them with various therapeutic molecules and alter tropism so they reach specific cellular targets. exoIL-12 is currently being evaluated in a Phase 1 clinical trial in patients with cutaneous T cell lymphoma and is one of two Codiak programs in human clinical testing. M2 phenotype macrophages promote tumor growth by creating a highly immunosuppressive environment in the tumor. exoASO-STAT6 is a novel therapeutic candidate designed to deliver antisense oligonucleotides to selectively target STAT6, a key immunosuppressive transcription factor in tumor associated macrophages. Codiak plans to focus clinical development of exoASO-STAT6 initially in myeloid rich cancers such as colorectal cancer, hepatocellular carcinoma and others. Results from multiple in vitro and in vivo studies demonstrate that exoASO-STAT6 effectively reprograms macrophages to a pro-inflammatory M1 phenotype, resulting in potent single-agent anti-tumor activity. exoASO-STAT6 exhibits a selective tropism for myeloid cells and delivered up to 12-fold more ASO to M2 macrophages in vivo than ASO administration without an exosome. In vivo studies with exoASO-STAT6 in two syngeneic tumor models consistently demonstrated potent single-agent activity. Monotherapy with exoASO-STAT6 resulted in 60% complete tumor remission in CT26 tumors. Notably, free STAT6 ASO showed no anti-tumor activity at the same dose, highlighting the enhancement in ASO therapeutic efficacy conferred by exosomes. Intravenous administration of exoASO-STAT6 in mice bearing Hepa1-6 orthotopic HCC tumors also resulted in profound reduction of tumor burden. In contrast, anti-CSF1R or anti-PD1 therapy as a comparator did not result in any measurable effects on tumor growth in either model. In both tumor models, monotherapy activity of exoASO-STAT6 is accompanied by a substantial remodeling of the tumor microenvironment, as evidenced by marked increase in pro-inflammatory markers such as iNOS positive monocyte/macrophages, one of the hallmarks of effective M1 macrophage reprogramming, and reduction in immunosuppressive markers such as CD163. Subsequent genetic and histology analyses confirmed remodeling of the TME to a pro-inflammatory M1-like phenotype induced by exoASO-STAT6 therapy. IL-12 is a potent anti-tumor cytokine; however, translating IL-12 into a drug in the clinic has generally been hindered by significant safety and tolerability concerns. To overcome these limitations, exoIL-12 was designed to facilitate dose control of IL-12 and limit systemic exposure and associated toxicity by localizing IL-12 in the TME to potentially expand the therapeutic index. Previously reported pharmacokinetic and pharmacodynamic data from the randomized, placebo controlled, double-blind Phase 1 study showed that administration of exoIL-12 in healthy volunteers resulted in a favorable safety and tolerability profile and prolonged pharmacodynamic effect with no local or systemic treatment-related adverse events and no detectable systemic exposure of IL-12. In particular, a subcutaneously administered single ascending dose of exoIL-12 demonstrated no systemic exposure across the dose range, which is in direct contrast to previous clinical studies with recombinant IL-12. New pharmacodynamic data presented at AACR 2021 show no systemic IFN-gamma production, which may further explain the favorable safety and tolerability of exoIL-12. Pharmacodynamic data from skin punch biopsies showed detectable levels of exoIL-12 in the skin at the 6.0 undefined dose as much as 24 hours post injection, indicating retention at the injection site and prolonged activation of the IL-12 signaling cascade. Based on these findings, the 6.0 undefined dose level has been selected for the second portion of the Phase 1 trial currently underway, where the safety and efficacy of exoIL-12 will be evaluated following repeat doses into the lesions of patients with early-stage CTCL.

15:39 EDT Kezar Life Sciences presents preclinical data with IND candidate KZR-261 - Kezar Life Sciences presented preclinical data on the company's novel protein secretion program during two poster sessions at the American Association for Cancer Research 2021 Virtual Annual Meeting. Kezar examined the activity of KZR-261, a small molecule inhibitor of the Sec 61 translocon, and a closely related representative molecule in hundreds of tumor cell lines. The objective was to compare drug activity and identify sensitivity to gene mutations and impact on gene expression levels. No single gene predicted the activity of KZR-261, consistent with the known impact of KZR-261 on multiple targets. However, representative gene modules identified through mechanism agnostic analysis were associated with sensitivity in tumor cells and show high overlap with key processes involved in protein secretion. Analyses of primary tumor and tissue expression datasets predict that many tumor types will be more sensitive than normal tissues and cells. Global proteomic profiling of protein secretion in tumor cells and non-transformed cells was also conducted. KZR-261 and the related molecules reduce expression of Sec61 clients, namely secreted and transmembrane proteins. In tumor cells, these compounds reduced expression of approximately 10% of Sec61 clients by at least two-fold. However, in non-transformed cells, KZR-261 inhibited the expression of less than 5% of measured Sec61 clients, many of which can be measured from clinical samples in future clinical trials. Pending successful completion of drug product manufacturing, submission of an Investigational New Drug application is anticipated in mid-2021. A first-in-human Phase 1 study to evaluate the safety and anti-tumor activity of KZR-261 in patients with solid tumors is expected to commence shortly thereafter.

15:34 EDT Xencor presents data from preclinical XmAb Bispecific antibody/cytokine programs - Xencor announced the presentation of new data from multiple preclinical XmAb bispecific antibody programs and its preclinical IL-12-Fc cytokine program at the American Association for Cancer Research Annual Meeting, being held virtually April 10-15, 2021. According to Abstract 1743, "IL12 heterodimeric Fc-fusions engineered for reduced potency exhibit strong anti-tumor activity and improved therapeutic index compared to native IL12 agents," IL-12 is a potent proinflammatory cytokine produced by activated antigen-presenting cells, and it leads to proliferation of T cells and NK cells and increased cytotoxicity through high levels of interferon gamma signaling. As a potent immune stimulating protein, IL-12 can have a significant effect on shrinking tumors; however, prior clinical studies have demonstrated it to have a narrow therapeutic window, limiting potential response rates. Xencor's IL-12-Fc cytokine program builds on the company's prior work with IL-15-Fc cytokines in oncology, where reduced potency led to improved pharmacokinetics, pharmacodynamics and tolerability in preclinical studies. IL-12-Fc fusions were engineered with reduced potency in order to improve potential tolerability, slow receptor-mediated clearance and prolong the molecules' half-lives, compared to native IL-12. The potency-reduced IL-12-Fc fusions demonstrated significant anti-tumor activity in vivo concurrent with activation and proliferation of CD8+ T cells and increased levels of interferon gamma in serum. In non-human primates, the engineered cytokines had an improved pharmacokinetic profile and therapeutic window compared to a native cytokine-Fc fusion, with superior exposure, a more gradual dose response and similar levels of cytokine production in serum. According to Abstract: 1880, "PDL1-targeted CD28 costimulatory bispecific antibodies enhance T cell activation in solid tumors," Xencor engineered PD-L1 x CD28 bispecific antibodies to provide conditional co-stimulation of T cells, activating them when bound to tumor cells. PD-L1, which is expressed on many types of tumors, suppresses anti-tumor responses by the immune system and has been shown to directly inhibit CD28 co-stimulation. A PD-L1 x CD28 bispecific antibody, therefore, may promote CD28 co-stimulation and simultaneously block CD28's suppression by PD-L1. In vitro, the combination of the PD-L1 x CD28 and a CD3 T cell engager enhanced T cell activation and proliferation compared to the CD3 bispecific alone, as designed. PD-L1 x CD28 also enhanced the interaction between T cells and antigen presenting cells and exhibited strong CD28-dependent anti-tumor activity in mice. PD-L1 x CD28 was well tolerated in non-human primates and exhibited favorable pharmacokinetics. According to Abstract: 1860, "Bispecific claudin-6 x CD3 antibodies in a 2+1 format demonstrate selectivity and activity on human ovarian cancer cells," Claudin-6 is a tumor-associated antigen overexpressed in ovarian cancer and other solid tumors, and its differential expression in cancerous tissue makes CLDN6 an intriguing target for CD3 bispecific antibodies. Many members of the claudin family, which are small transmembrane proteins, have high sequence identity, which complicates selectivity among claudins. CLDN6 x CD3 bispecific antibodies were engineered in the XmAb 2+1 format, and the tumor binding domain was further engineered for improved selectivity of CLDN6 over similar claudin family members, such as CLDN9. In preclinical models, CLDN6 x CD3 bound more preferentially to tumor cells compared to cell lines with normal tissue CLDN9 expression levels. Lead candidates demonstrated reversal of tumor growth in human-cell engrafted mouse models of ovarian cancer. Further data from non-human primate studies demonstrated the candidates were well-tolerated with favorable pharmacokinetic profiles. According to Abstract: 1831, "Affinity tuned XmAb 2+1 GPC3 x CD3 bispecific antibodies demonstrate selective activity in liver cancer models," GPC3 is an antigen associated with hepatocellular carcinoma, squamous cell carcinoma of the lung and other cancers. Under certain conditions, GPC3 can trigger Wnt signaling and promote tumor proliferation. Despite a favorable expression profile, unfavorable tolerability has been reported from multiple clinical studies evaluating CAR-T therapy and T cell engaging bispecific antibodies that target GPC3. GPC3 x CD3 bispecific antibodies in the XmAb 2+1 format selectively recruited T cells to kill high GPC3-expressing cancer cells and avoided cytotoxicity to a low GP3C-expressing cell line. A comparison of GPC3 x CD3 bispecific antibodies with the XmAb 2+1 format and first-generation T cell engagers demonstrated similar anti-tumor activity and immune cell proliferation in vitro.

15:20 EDT Bristol-Myers announces results from CheckMate -816 study - Bristol Myers Squibb announced results from the CheckMate -816 study, which showed that neoadjuvant treatment with three cycles of Opdivo plus chemotherapy "significantly improved" pathologic complete response, a primary endpoint, compared to chemotherapy alone in patients with resectable stage Ib to IIIa non-small cell lung cancer. In the study, 24% of patients treated with Opdivo plus chemotherapy prior to surgery achieved pCR, compared to 2.2% of patients treated with chemotherapy alone, with pCR defined as no evidence of cancer cells in their resected tissue as assessed by a blinded independent pathology review. Additionally, Opdivo plus chemotherapy was well tolerated and showed consistent improvements in pCR regardless of PD-L1 expression levels, histologies or stages of disease. Opdivo plus chemotherapy also demonstrated improvements in key secondary endpoints, including major pathological response. Four times as many patients treated with Opdivo plus chemotherapy vs. chemotherapy alone achieved MPR, meaning 10% or less of their tumor cells remained after neoadjuvant therapy. Three cycles of Opdivo plus chemotherapy were associated with a tolerable safety profile, and no new safety signals were observed. Grade 3-4 treatment-related adverse events were reported in 34% vs. 37% in the Opdivo plus chemotherapy vs. chemotherapy alone arms, respectively. Surgery was rarely canceled due to adverse events, only affecting two patients in each arm of the trial. Further, in this trial, more patients who received neoadjuvant Opdivo plus chemotherapy underwent surgery, showing that the addition of Opdivo did not decrease the feasibility of performing surgery. In addition, the number of patients whose tumors were completely resected was higher with Opdivo plus chemotherapy vs. chemotherapy. Rates of surgery-related adverse events were similar between the two treatment arms.