On November 12, 2021 Intensity Therapeutics, Inc. ("Intensity"), a clinical-stage biotechnology company focused on the discovery and development of proprietary immune-based intratumoral cancer therapies designed to kill tumors and increase immune system recognition of cancers, reported that data from its open-label Phase 1/2 study of novel lead asset, INT230-6, as a monotherapy or in combination with ipilimumab in adult subjects with metastatic sarcomas, is being presented today, in an oral presentation, at the Connective Tissue Oncology Society Virtual Annual Meeting (CTOS) (Press release, Intensity Therapeutics, NOV 12, 2021, View Source [SID1234595486]).

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"Preliminary data suggests that INT230-6, as a monotherapy, demonstrates direct tumor killing in soft tissue sarcoma subjects (STS) and elicits an anti-cancer immune response within the injected tumor," stated poster presenter and study investigator, Matthew A. Ingham, MD, Assistant Professor of Medicine in the Division of Hematology and Oncology at Columbia University Vagelos College of Physicians and Surgeons and first author of the study. "To date, though in a limited number of patients, INT230-6 treatment related adverse events are mostly low grade and the drug is well-tolerated either as a monotherapy or in combination with checkpoint inhibitor, ipilimumab. Additionally, an exploratory analysis showed an increase in survival with dosing a volume of INT230-6 above forty percent of the total tumor burden, as compared to survival from historical sarcoma studies. These results provide further evidence to continue studying this novel therapeutic drug approach."

Lewis H. Bender, President and Chief Executive Officer of Intensity Therapeutics, added, "The promising data supports our belief that INT230-6, a locally-delivered anti-cancer product candidate, may potentially lead to clinical benefit with lower levels of off target side effects compared to chemotherapies for patients with advanced soft tissue sarcomas. Given these results, earlier this year we met with and reached alignment with FDA of the design of a randomized Phase 3 trial, subject to review by the Agency of the final protocol, to evaluate INT230-6 versus standard of care in patients with advanced soft tissue sarcomas."

Title: Safety and Efficacy from a Phase 1/2 Study of Intratumoral INT230-6 Alone or In Combination with Ipilimumab [INTENSITY# IT-01; BMS# CA184-592] in Adult Subjects with Metastatic Sarcomas (NCT 03058289)

The presentation will be accessible on the "Publications, Papers and Posters" section of Intensity’s website at: View Source

The data presented included results from 19 patients with different metastatic sarcomas treated with INT230-6 either as a monotherapy (n=10), or in combination with a checkpoint inhibitor (n=8) primarily ipilimumab. The enrolled patients’ cancer progressed following a median of three prior lines of therapy (range 0 to 9) including all approved, appropriate therapies for a subject’s particular cancer. Demographics were similar in subjects enrolled in monotherapy and checkpoint inhibitor combination arms. The cumulative dose of INT230-6 IT injections ranged from 20 to 530mL (265mg cisplatin, 53mg vinblastine), with repeated intratumoral injections in multiple tumors. Pharmacokinetic (PK) profile analysis from 18 STS subjects in study IT-01 were analyzed for cisplatin, SHAO and vinblastine and show less than 5% of the drugs enter the blood stream.

A retrospective exploratory analysis of subjects was assessed by comparing INT230-6 dosed at greater than or equal to 40% of their incoming total tumor burden, suggesting promising survival. For sarcoma subjects dosed to >40% of their total tumor burden, approximately 60% of subjects will be alive at 1 year. These results compare favorably to those seen in historical Phase 1/2 studies of sarcoma subjects where approximately 50% of subjects are deceased at 3 to 8 months depending on certain prognostic factors (ECOG, LDH, # of metastatic sites). Abscopal effects were seen in visceral lesions in two subjects, which may be an underestimation, as no tumors under 1 cm and not all larger lesions were followed.

Immunohistochemistry analysis of INT230-6 monotherapy paired (pre- and 28 days post-dose) biopsy of injected lesions from 3 INT230-6 monotherapy STS subjects showed a median of 60% reduction in tumor cell content and a 72% reduction in Ki67 staining (proliferation marker).

Hematoxylin and Eosin assessments demonstrated substantial reductions of cancer cells in biopsies from monotherapy subjects after two injections of INT230-6 when compared to baseline. Local delivery of INT230-6 as monotherapy into tumors induced an immune response with increases of activated CD4+ and CD8+ T-cells in the tumor with a few low grade immune-related adverse events. These clinical results are consistent with immune findings from in vivo models. Most other adverse events were low grade and transient, consisting mostly of pain at the injection site (68.4% of patients), fatigue (42.1%) or decreased appetite (36%). There were no grade 4 or 5 treatment emergent adverse events and no events that were dose limiting.

About INT230-6

INT230-6, Intensity’s lead proprietary investigational product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRx℠ technology platform. The drug is composed of two proven, potent anti-cancer agents, cisplatin and vinblastine, and a penetration enhancer molecule that helps disperse the drugs throughout tumors for diffusion into cancer cells. In addition to local disease control, direct killing of the tumor by INT230-6 creates neoantigens leading to engagement of the immune system and systemic anti-tumor effects in the tumor. Importantly, these effects are mediated without the immunosuppression of concomitant systemic chemotherapy.

INT230-6 is currently being evaluated in several Phase 2 cohorts (NCT03058289) in patients with various advanced solid tumors as part of Study IT-01. In 2019, the Company signed a clinical collaboration agreement with Merck Sharpe & Dohme (Merck) to evaluate the combination of INT230-6 and KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 (programmed death receptor-1) therapy, in patients with advanced pancreatic, colon, squamous cell and bile duct malignancies. In 2020, the Company executed a clinical collaboration agreement with Bristol-Myers Squibb Company to evaluate the combination of INT230-6 with Bristol-Myers Squibb’s anti-CTLA-4 antibody, Yervoy (ipilimumab), in patients with advanced liver, breast and sarcoma cancers. In 2021, the Company executed agreements with the Ottawa Hospital Research Institute and the Ontario Institute of Cancer Research to study INT230-6 in a randomized controlled neoadjuvant Phase 2 study in women with early stage breast cancer (the INVINCIBLE study) (NCT04781725).

On November 12, 2021 Sorrento Therapeutics, Inc. (Nasdaq: SRNE, "Sorrento") reported the peer-reviewed publication of significant results from a pivotal study of abivertinib on 227 heavily pretreated NSCLC patients in the journal Clinical Cancer Research, authored by Dr. Yi-Long Wu, distinguished professor of Guangdong Lung Cancer Institute, awardee of the prestigious "International Association for the Study of Lung Cancer (IASLC) Scientific Award" in 2017, and the principal investigator of the study (Press release, Sorrento Therapeutics, NOV 12, 2021, View Source [SID1234595509]).

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The full manuscript is available at: View Source

Abivertinib is a pyrrolopyrimidine-based, third-generation EGFR/BTK inhibitor, which is structurally distinct from osimertinib. Abivertinib selectively inhibits EGFR-activating and resistant mutation with nearly 300-fold potency as compared with wild-type EGFR. The 300 mg BID abivertinib dose was based upon the pharmacokinetics, efficacy and safety profiles characterized in prior studies. In the pivotal study, 227 patients received this dose for a median treatment duration of 24.6 weeks (0.43-129). Among 209 response evaluable patients, confirmed ORR was 52.2% (109/209; 95% CI: 45.2%, 59.1%) and the DCR was 88.0% (184/209, 95% CI: 82.9%, 92.1%). The median DoR and PFS were 8.5 months (95% CI: 6.1, 9.2) and 7.5 months (95% CI: 6.0, 8.8), respectively. The median OS was 24.9 months (95% CI: 22.4, NR). All patients (N=227) reported at least 1 AE, with 96.9% (220/227) reporting treatment-related AEs. Treatment-related serious AEs were reported in 13.7% (31/227) of patients. Death was reported in 4.4% (10/227) of patients, and none was deemed related to abivertinib.

With the ORR of 52.2%, and OS of 24.9 months, comparable to approved 3rd generation EGFR inhibitors, abivertinib demonstrated significantly efficacious effects in overcoming resistant mutation in NSCLC. Based on these results, Sorrento is conducting an independent review process with long-term follow up data and intends to request a pre-NDA meeting with FDA. "We are very encouraged by the publication of these significant positive results of abivertinib on the treatment of advanced and heavily pretreated NSCLC lung cancer in Clinical Cancer Research and look forward to bringing abivertinib into the armamentarium of this multi-billion dollar indication," said Dr. Henry Ji, Chairman and CEO of Sorrento.

On November 12, 2021 Bolt Biotherapeutics, Inc. (Nasdaq: BOLT), a clinical-stage biotechnology company pioneering a new class of immuno-oncology agents that combine the targeting precision of antibodies with the power of both the innate and adaptive immune systems, reported the company will be presenting posters with new data from three of its pipeline programs on Saturday, Nov. 13, at the 2021 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting, being held virtually and in person in Washington, D.C. from Nov. 10-14 (Press release, Bolt Biotherapeutics, NOV 12, 2021, View Source [SID1234618693]). Each presentation highlights the progress made in preclinical studies to demonstrate the potential for each pipeline candidate as a novel approach for the treatment for cancer.

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"We are presenting new data for three of our pipeline programs that demonstrate the depth of our technology platform and the expertise of our team in modulating myeloid cell biology to develop promising therapeutic candidates," said David Dornan, Ph.D., Bolt Biotherapeutics’ Chief Scientific Officer. "Repolarizing tumor-associated macrophages, or TAMs, to become tumor destructive via the novel target Dectin-2 is groundbreaking work that may be synergistic with our entire Boltbody ISAC portfolio. Our work targeting CEA and PD-L1 reinforces our commitment to develop therapeutics that could have promising activity against solid tumors where limited treatment options are available."

Highlights of the three poster presentations follow, and copies of the posters are available on the Bolt Biotherapeutics website.
Poster #784: "BDC-2034: Discovery of a CEA-targeting Immune-Stimulating Antibody Conjugate (ISAC) for Solid Tumors"
Presenter: William G. Mallet, Ph.D.
Details: Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hall

Key findings from the study:
CEA is a well-validated tumor antigen for the development of targeted therapies addressing multiple types of solid tumors, such as colon cancer, where new treatment options are urgently needed. Given the abundance of innate immune cells in CEA-expressing cancers, innate immune stimulation presents a promising therapeutic strategy. Applying Boltbody platform technology, Bolt Biotherapeutics scientists have developed a novel CEA-targeted ISAC, BDC-2034, to exploit over-expression of CEA in cancers. BDC-2034 is designed to trigger the innate immune system, leading to adaptive anti-tumor immunity and tumor destruction.

BDC-2034 comprises a novel CEA-targeted, pro-phagocytic antibody conjugated to a proprietary TLR7/8 agonist payload. Both elements of this molecule are finetuned for selective immune activation in tumors.
New data reported at SITC (Free SITC Whitepaper) 2021 demonstrate both tumor cell clearance and innate immune activation in cellular and in vivo models of CEA-expressing cancers. Further, systemic administration in tumor-bearing animals results in tumor-selective immunity.
Based on these data, Bolt Biotherapeutics designated BDC-2034 as a clinical candidate and is currently conducting IND-enabling studies with the expectation to initiate BDC-2034 clinical development in 2022.
Poster #782: "PD-L1-targeted ISAC combines myeloid cell activation, immune-checkpoint inhibition and ADCP to improve anti-tumor efficacy over anti-PD-L1 antibodies in preclinical models"
Presenter: Marcin Kowanetz, Ph.D.
Details: Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hall

Key findings from the study:
Bolt Biotherapeutics scientists are presenting for the first time preclinical data on a novel multifunctional PD-L1-targeted Boltbody ISAC that has demonstrated the potential to improve upon the efficacy of PD-L1/PD-1 inhibition, especially in tumor types that do not respond well to immune-checkpoint inhibition.

Bolt Biotherapeutics’ PD-L1 ISAC uniquely combines three mechanisms of action: the ADCP and myeloid cell activation of an ISAC, plus immune-checkpoint inhibition with the ability to act through PD-L1 expressed on both tumor and immune cells.
Data presented at SITC (Free SITC Whitepaper) 2021 demonstrate how PD-L1 ISAC induces robust, target-dependent activation of the immune system, including induction of immunological memory.
Treatment with PD-L1 ISACs led to an effective anti-tumor response that was substantially improved over PD-L1 antibody blockage in preclinical models.
Poster #862: "Dectin-2, a novel target for tumor macrophage reprogramming in cancer immunotherapy"
Presenter: Justin A. Kenkel, Ph.D.
Details: Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hall

Key findings from the study:
For the first time, Bolt Biotherapeutics is presenting data providing preclinical validation of Dectin-2, formerly referred to as TAM1, as a novel target for cancer immunotherapy. Expressed by tumor-associated macrophages (TAMs), Dectin-2 is a pattern recognition receptor that stimulates proinflammatory cytokine production and antigen presentation to drive innate and adaptive immune responses.

Findings reported at SITC (Free SITC Whitepaper) 2021 demonstrate that agonism of Dectin-2 on TAMs elicits secretion of pro-inflammatory cytokines and chemokines capable of invoking productive anti-tumor immunity.
In murine tumor models, Dectin-2 agonism mediates anti-tumor efficacy in a CD8 T cell-dependent manner and induces immunological memory against the tumor.
Bolt Biotherapeutics scientists have generated Dectin-2 agonist antibodies that show the potential to reprogram tumor-supportive macrophages into tumor-destructive macrophages.
About the Boltbody Immune-Stimulating Antibody Conjugate (ISAC) Platform
ISACs are a new category of immunotherapy that combines the precision of antibody targeting with the strength of the innate and adaptive immune systems. Boltbody ISACs comprise three primary components: a tumor-targeting antibody, a non-cleavable linker, and a proprietary immune stimulant to activate the patient’s innate immune system. By initially targeting a single marker on the surface of a patient’s tumor cells, an ISAC can create a new immune response by activating and recruiting myeloid cells. The activated myeloid cells start a feed-forward loop by releasing cytokines and chemokines, chemical signals that attract other immune cells and lower the activation threshold for an immune response. This reprograms the tumor microenvironment and invokes an adaptive immune response that targets the tumor, with the goal of durable responses for patients with cancer.

On November 12, 2021 Senti Bio, a leading gene circuit company, reported results from SENTI-401, one of its preclinical stage oncology programs, that aims to more precisely target tumors while sparing healthy cells (Press release, Senti Biosciences, NOV 12, 2021, View Source [SID1234596740]). The poster presentation, which is on display starting today at the Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), describes preclinical data from SENTI-401, a Logic Gated allogeneic, chimeric antigen receptor natural killer (CAR-NK) cell therapy development program for the treatment of colorectal cancer (CRC). The results support the Company’s vision of using gene circuits to create next-generation, "smart" cell and gene therapies with computer-like logic in human cells.

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Targeting of tumor-associated antigens, such as carcinoembryonic antigen (CEA), can result in severe clinical toxicities due to the killing of healthy epithelial cells whose cell surfaces also express CEA. This includes toxicity risk to cells in the colon and gastrointestinal tract as well as the lungs. SENTI-401 is designed to incorporate logic gating to target and kill CEA-expressing tumor cells, while preventing the killing of CEA-expressing healthy epithelial cells. The SENTI-401 NOT GATE pairs a CEA-targeting activating-CAR (aCAR) with an inhibitory-CAR (iCAR) that recognizes a safety antigen (SA) uniquely expressed in certain healthy gastrointestinal and lung epithelial cells. The SA was identified and validated through Senti Bio’s proprietary Bioinformatics-Driven Antigen Pairing (B-DAP) discovery platform. The poster highlights the SENTI-401 development program’s NOT GATE gene circuit technology as follows:

Killing of colorectal cancer cells:

Generated, tested and optimized anti-CEA CAR constructs for optimal performance in NK cells using Senti Bio’s Design-Build-Test-and-Learn (DBTL) platform.
Evaluated CAR-NK cells for anti-tumor activity, and demonstrated potent killing of CEA-expressing CRC target cells in vitro. A single dose of these CAR-NK cells also demonstrated anti-tumor activity in a human CRC xenograft model, reducing tumor burden in >33% of the treated mice.

Preservation of healthy cells:

iCAR suppressed aCAR mediated killing (p<0.05) in a SA-dependent manner without diminishing aCAR-mediated anti-tumor activity.
V-set and Immunoglobulin Domain Containing 2 (VSIG2), a membrane protein, was identified as the SA via Senti Bio’s B-DAP discovery platform and validated in healthy tissue samples. VSIG2 is uniquely expressed in CEA-positive healthy cells but not in tumor cells.
Used Senti Bio’s DBTL platform to evaluate multiple iCAR designs that utilize inhibitory domains that can selectively prevent CAR-mediated killing in an SA-dependent manner.

"Existing cancer therapies generally target only a single tumor-associated antigen, which means that they can only be used safely and effectively where that antigen is expressed primarily on tumor cells," said Alba Gonzalez, PhD, presenter of the abstract and Associate Director, Research at Senti Bio. "What is so exciting about our Logic Gating platform is the potential to advance a highly novel approach to CAR-NK based therapy that may more precisely treat colon cancer, and other solid tumors, with a reduced risk for on-target, off-tumor toxicities, thereby offering the potential to increase the therapeutic window and provide meaningful benefit to patients."

The abstract (Poster #116) is available on the SITC (Free SITC Whitepaper) website. The poster is available on the Senti Bio website.

About Logic Gating and NOT GATE Gene Circuits
Logic Gating gene circuits are designed to enable cell and gene therapies to control their therapeutic activity in response to the presence or absence of multiple disease biomarkers. NOT GATE gene circuits are one type of Logic Gates that are designed to widen the therapeutic window by enabling killing of cancer cells while preserving healthy cells. The NOT GATE functions by recognizing Safety Antigens on the cell surface, or antigens that are selectively expressed on healthy cells and not on cancer cells, thus limiting on-target, off-tumor killing. By protecting healthy cells, the NOT GATE has the potential to enable more effective on-target, on-tumor killing of tumor cells that express tumor-associated antigens.

On November 12, 2021 Dr Olga Kondrashova from the Medical Genomics Lab at QIMR Berghofer reported that it has been awarded a $650,740 Investigator grant from the National Health and Medical Research Council (Press release, QIMR Berghofer Medical Research Institute, NOV 12, 2021, View Source [SID1234595267]).

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Dr Kondrashova will use genomic technologies to study molecular portraits of cancers including ovarian and breast cancers with faulty DNA repair to better understand how to prevent drug resistance and treat each cancer most effectively.

This important work linking cancer genomics with patient treatment responses aims to improve cancer survival rates.

We are very grateful to the National Health and Medical Research Council for supporting our cancer genomics research initiatives.