On December 8, 2022 Instil Bio, Inc. ("Instil" or the "Company") (NASDAQ: TIL), a clinical-stage biopharmaceutical company focused on developing next-generation tumor infiltrating lymphocyte, or TIL, therapies for the treatment of patients with cancer, reported a reprioritization of its clinical programs to focus on development of its CoStAR-TIL product candidates (Press release, Instil Bio, DEC 8, 2022, View Source [SID1234624929]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"From the beginning of Instil, we have been committed to advancing TIL therapy by enhancing the native activity of TILs with innovative strategies designed to improve product efficacy and safety," said Bronson Crouch, CEO of Instil Bio. "Although it was a difficult decision to discontinue the development of ITIL-168, this decision provides us the opportunity to accelerate the development of CoStAR and other novel technologies to enhance TIL therapies for patients. We are excited to resume dosing patients in the Phase 1 ITIL-306 study and anticipate providing initial data readouts next year."

Strategic Update

Instil has prioritized development of its proprietary, genetically-engineered CoStAR-TIL programs, which are designed to boost the efficacy of T cells by providing potent synthetic costimulatory signals within the tumor microenvironment (TME). Instil’s lead CoStAR-TIL program, ITIL-306, is in a Phase 1 dose escalation trial in non-small cell lung cancer ("NSCLC"), ovarian cancer, and renal cell carcinoma, with the first patient dosed earlier this year. The Company expects to report data from the dose escalation cohorts of the Phase 1 ITIL-306 study in 2023.

Instil is undertaking a reduction in its U.S. workforce of approximately 60% to re-align its operating model from a registration-focused company to a development-stage company.

ITIL-168 Program Update

Instil is discontinuing its ITIL-168 clinical programs, the DELTA-1 trial in advanced melanoma and the DELTA-2 trial in NSCLC, cervical cancer, and head and neck squamous cell carcinoma. After an analysis of the potential scenarios to restart and complete a registration-enabling cohort in advanced melanoma in the DELTA-1 trial, the Company has decided to prioritize the CoStAR-TIL platform.

On December 8, 2022 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or the "Company"), a leader in the development of targeted radiotherapies, reported that it has entered into a research collaboration with Columbia University to study Actimab-A, its clinical-stage CD33 targeting radiotherapeutic, with engineered hematopoietic stem cells (eHSCs) modified by CRISPR/Cas9 gene editing technology to knock out CD33 expression (Press release, Actinium Pharmaceuticals, DEC 8, 2022, View Source [SID1234624928]). Dr. Siddhartha Mukherjee, MD, DPhil, Assistant Professor of Medicine at Columbia University Medical Center in the Department of Medicine and Division of Hematology/Oncology and his research group developed the technology. Technology from Dr. Mukherjee’s lab has been licensed and is currently being developed by Vor Biopharma, Inc., including trem-cel (formerly VOR33). Vor is currently using Mylotarg, a CD33 targeting antibody drug conjugate (ADC), in its clinical trial to target residual CD33 positive leukemia cells post-transplant.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Dr. Siddharth Mukherjee, MD, DPhil, stated, "I am very excited to be collaborating with Actinium to study Actimab-A targeted radiotherapy with our eHSCs to prevent relapse and improve post-transplant outcomes. Actimab-A is highly differentiated from other CD33 targeting agents including the ADC Mylotarg, which demonstrates resistance with repeated use. Actimab-A due to its radiation modality is agnostic to cytogenetics and molecular mutations and the Actinium-225 warhead can produce double strand DNA breaks for which there is no known resistance or repair mechanism. With AML cells being highly sensitive to radiation, we believe Actimab-A has great potential given the potency of the Actinium-225 isotope warhead, its validated CD33 targeting ability and its strong clinical data to date. My team and I look forward to progressing this collaboration with Actinium to generate first ever data with a targeted radiotherapy following engineered HSC transplant to advance to this novel combination to the clinic."

Dr. Avinash Desai, Actinium’s Chief Medical Officer, added, "We are honored to be working with Dr. Mukherjee and his team at Columbia University in this exciting collaboration. This is another attractive setting for Actimab-A that builds on our leading-edge, combination focused development efforts that includes chemotherapy, targeted agents and immune checkpoint inhibitors. We are eager to show that Actimab-A will produce better post-eHSC transplant outcomes than other modalities including ADCs like Mylotarg given the specificity and potency of the Actinium-225 warhead. Recently, Actimab-A, in combination with the chemotherapy CLAG-M, produced deep remissions by wiping out residual leukemia cells resulting in high rates of MRD negativity rate in very difficult to treat relapsed or refractory AML patients, including patients with TP53 mutations and those receiving multiple lines of prior therapy including Venetoclax. These results give us confidence that Actimab-A will effectively eliminate any residual leukemia cells in this post-transplant setting where the leukemia burden is expected to be much lower. In addition to improved leukemia cell killing, Actimab-A’s highly targeted nature has been shown to be well tolerated with minimal extramedullary toxicities. We look forward the oral presentation at ASH (Free ASH Whitepaper) and to advancing this collaboration and furthering Actimab-A’s utility in treating patients with AML."

Under this collaboration, Actimab-A will be administered following transplantation of the eHSCs with the goal of eliminating any CD33 positive residual AML cells. eHSCs are intended to engraft and reconstitute patients’ blood and immune systems with cells that do not express cancer-specific targets such as CD33. This would then allow a patient to receive CD33 targeting therapy post-transplant to eradicate any residual CD33 positive leukemia cells and prevent relapse while sparing newly formed blood cells that do not express CD33. Actimab-A has been studied in over 150 AML patients in six clinical trials. It has the most clinical experience of any Actinium-225 based drug candidate in development. Actinium-225 is an alpha-particle emitting radioisotope that has the most potent cell killing ability of any medical grade isotope but has a short pathlength that limits potential off-target effects. Recently, Actimab-A demonstrated high rates MRD negativity following CLAG-M therapy in relapsed or refractory AML patients with adverse risk features including over 50% with a TP53 mutation and over 50% who received prior treatment with Venetoclax. This resulted in a 53% 1-year overall survival and 32% 2-year overall survival in a patient group that has an expected overall survival of less than 3 months.

On December 8, 2022 Sensei Biotherapeutics, Inc. (Nasdaq: SNSE), an immuno-oncology company focused on the discovery and development of next-generation therapeutics for cancer patients, reported that a streamlining and realignment of resources to support its key indications and programs, including its lead antibody, SNS-101, a conditionally active antibody targeting the immune checkpoint VISTA, as well as its other TMAb (Tumor Microenvironment Activated biologics) platform programs (Press release, Sensei Biotherapeutics, DEC 8, 2022, View Source [SID1234624927]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In connection with this announcement, the Company will close its research site in Boston and reduce its total workforce by approximately 40%. The Company expects that such reduction in operating expenses, including employee-related costs and reduced occupancy costs, will extend Sensei’s estimated cash runway into the second half of 2025.

The Company will maintain its Rockville, Maryland research facility, where antibody discovery and production in support of SNS-101 and other TMAb programs is conducted, while maintaining a smaller business office in the Boston area. Sensei plans to relocate any ongoing work at its Boston research site to its Rockville, Maryland site.

"Our Board of Directors and management team remain focused on ensuring that Sensei is well positioned to execute on our near-term clinical and preclinical milestones. As we continue to progress the development of SNS-101 towards an IND in the coming months, we have made the strategic decision to reduce our early-stage R&D expenses related to certain discovery stage targets to more closely align with our strategic and financial goals," said John Celebi, President and Chief Executive Officer of Sensei Biotherapeutics. "Today’s announcement follows a thoughtful decision-making process, where we ultimately determined that it is in the best interests of the Company to invest our resources where we believe they will have the greatest potential near-term impact. Decisions that impact our people are always extremely difficult, and I would like to express my gratitude to our departing employees for their hard work and service. We are committed to providing support for our impacted colleagues and to helping them identify other opportunities during this transition."

In conjunction with these announcements, Robert Pierce, M.D., Sensei’s Chief R&D Officer, will move to a consulting role as a Science Fellow, effective December 7, 2022, and Edward van der Horst, Ph.D., Sensei’s Senior Vice President, Biologics Discovery & Early Development, has been promoted to Chief Scientific Officer, effective December 7, 2022.

Dr. Edward van der Horst, Ph.D. has over 20 years of research and development experience with a strong focus on antibody drug development across diverse target classes in oncology. He has been instrumental in the discovery and development of several clinical-stage therapeutic antibodies, including a first-generation anti-VISTA antibody that is currently in clinical trials as well as the first clinical stage anti-HER3 antibody. During his time at Sensei, Dr. van der Horst has overseen the discovery and early development of SNS-101, Sensei’s conditionally active anti-VISTA antibody, as well as other TMAb platform drug programs. Prior to joining Sensei in 2019, Dr. van der Horst worked at Zenith Epigenetics Ltd., Igenica Biotherapeutics Inc., OncoMed Pharmaceuticals, Tularik, Inc. (now Amgen) and U3 Pharma GmbH (now Daiichi-Sankyo). Dr. van der Horst earned his Ph.D. in biochemistry from the Max-Planck Institute of Biochemistry and conducted his master’s thesis at Max-Planck Institute of Neurobiology. He graduated with an M.S. in chemistry from the Ludwig Maximilian University of Munich.

Sensei continues to advance SNS-101 through investigational new drug-enabling studies, and intends to submit an Investigational New Drug application (IND) in or prior to April 2023. The Company has reported differentiated preclinical data demonstrating anti-tumor effects, promising pharmacokinetic properties and a superior cytokine release profile compared with non-conditional anti-VISTA therapies. While it advances SNS-101 into the clinic in the near-term, Sensei will continue discovery work for its discovery-stage programs targeting VSIG-4 and ENTPDase1, also known as CD39.

On December 8, 2022 Jounce Therapeutics, Inc. (NASDAQ: JNCE), a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, reported new clinical data from the INNATE trial with JTX-8064 and pimi and the SELECT trial with vopra and pimi in two poster presentations at the ESMO (Free ESMO Whitepaper)-IO 2022 Annual Congress being held in Geneva, Switzerland (Press release, Jounce Therapeutics, DEC 8, 2022, View Source [SID1234624926]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

JTX-8064 is a highly selective and potent inhibitor of myeloid-specific Leukocyte Immunoglobulin Like Receptor B2 (LILRB2, also known as ILT4) with the potential to reverse PD-(L)1 inhibitor resistance. JTX-8064 is being studied in the INNATE trial (NCT04669899), a Phase 1/2 dose escalation/expansion trial of two investigational agents, JTX-8064 monotherapy (mono) and combination (combo) with pimi, Jounce’s investigational PD-1 inhibitor. Vopra is an inducible T cell costimulator (ICOS) agonist monoclonal antibody that stimulates CD4 T cells and may amplify anti-tumor activity. The SELECT trial is a randomized Phase 2 trial of vopra combined with pimi versus pimi monotherapy in TISvopra biomarker selected, immunotherapy naïve, 2nd line non-small cell lung cancer (NSCLC) patients.

In the poster titled "Phase 1 Study of JTX-8064, a LILRB2 (ILT4) inhibitor, as monotherapy and combination with pimivalimab (pimi), a PD-1 inhibitor (PD-1i), in patients (pts) with advanced solid tumors" Phase 1 data defining the recommended Phase 2 dose (RP2D) were presented. Patients with advanced solid tumors who progressed after all available therapy were treated at seven dose levels of JTX-8064 mono and two dose levels of JTX-8064 plus pimi 500 mg q3w using a Bayesian design. The study’s primary objectives are safety and determination of the RP2D. Secondary objectives are pharmacokinetics (PK), receptor occupancy (RO), and immunogenicity, and exploratory objectives include evaluation of anti-tumor activity including objective response rate (ORR) by RECIST 1.1 criteria.

Thirty-one patients were treated in dose escalation, 22 JTX-8064 mono, and nine JTX-8064 plus pimi. There were no dose limiting toxicities and maximum tolerated dose was not reached. Eleven monotherapy patients (50%) and six combination patients (66.7%) had treatment-related adverse events (TRAE), most of which were Grade 1 or 2, and there was only one serious TRAE, a tumor flare in the 1200 mg mono cohort. PK was linear. Full RO through 21 days was achieved at ≥ 300 mg resulting in selection of an RP2D of 700 mg q3w for JTX-8064 +/- pimi. Phase 1 efficacy data in the mono cohort (n=22): zero partial response (PR), seven (35%) stable disease (SD) including two durable SD (appendiceal cancer 8.3, ovarian cancer 12.2 months). Phase 1 efficacy data in the combo cohort (n=9): one confirmed PR (6.2 months) at 700 mg in a PD-1i resistant cholangiocarcinoma patient (PD-L1 score of 0) and resolution of both bone pain and cachexia, three (33%) SD with one durable SD of 6 months (PD-1i resistant NSCLC). Enrollment into multiple expansion cohorts is ongoing.

A poster titled "SELECT: A phase II randomized trial evaluating 2 doses of vopratelimab (V) + pimivalimab (P) vs P in TISvopra selected patients (pts)" of the vopra plus pimi SELECT trial included an update to data previously announced on clinical endpoints, including additional durability data for patients who remain on study. SELECT is a randomized Phase 2 trial (NCT04549025) evaluating vopra, Jounce’s ICOS agonist, in combination with pimi versus pimi alone in 69 immunotherapy naïve, second line, non-small cell lung cancer patients. Two hypotheses were tested in the study. First, two different doses were examined, both intended to result in different levels of pulsatile target engagement, which may optimize the dose of an agonist by reducing T cell exhaustion. Second, all patients in the study were selected by TISvopra, an 18 gene RNA tumor inflammation signature, previously associated with improved clinical outcomes in patients treated with vopra +/- nivolumab. Sixty nine (n=69) TISvopra positive patients with metastatic NSCLC after one prior platinum-containing regimen were randomized 2:1:1 to pimi monotherapy 1000 mg (n=36), vopra 0.1 mg/kg (n=18) plus pimi or vopra 0.03 mg/kg (n=15) q6w plus pimi.

Both doses of vopra demonstrated distinct patterns of pulsatile target engagement while vopra 0.03 mg/kg achieved a shorter duration of target engagement and a meaningful rest period from receptor saturation and signaling was observed. The low dose vopra combination trended favorably for the primary endpoint (percent change from baseline of all measurable lesions averaged over 9 and 18 weeks), ORR, and progression free survival (PFS). ORR was 40% (95% confidence intervals [CI]16.34, 67.71) for low dose vopra combination cohort, 27.8% (CI 14.20, 45.19) for pimi alone, and 16.7% (CI 3.58, 41.42) for high dose vopra combination cohort. Six month landmark PFS was 80% (CI 50, 93) for low dose vopra combination, 36% (CI 20, 53) for pimi monotherapy, and 31% (CI 11, 52) for high dose vopra combination. Benchmarks for approved PD-1 inhibitors in second line IO naïve NSCLC are ORR 18-20% and 6 month landmark PFS 30-38%. PD-L1 was evenly distributed across TISvopra patients and not associated with efficacy, suggesting TISvopra may select for patients who respond independent of PD-L1. Study treatment was well tolerated with 7.2% of patients reporting Grade ≥3 TRAEs. Most common TRAEs were Grade 1/2 hyperthyroidism and hypothyroidism.

Preclinical data demonstrating that a shorter period of target engagement with vopra in vitro stimulates T cells without the exhaustion seen with longer treatment was also summarized in the poster. This data provides a scientific rationale that clinical outcomes obtained with lower doses of vopra may be improved relative to doses that result in continuous target engagement, as the SELECT clinical data suggests. Jounce plans to pursue a partnership to enable further development of vopra 0.03 mg/kg in combination with a PD-1 inhibitor.

The posters will be available on the "Our Pipeline" section of the Jounce Therapeutics website after presentation at www.jouncetx.com.

About JTX-8064

JTX-8064 is a humanized IgG4 monoclonal antibody designed to specifically bind to Leukocyte Immunoglobulin Like Receptor B2 (LILRB2/ILT4) and block interactions with its ligands. JTX-8064 is the first tumor-associated macrophage candidate developed from Jounce’s Translational Science Platform. Preclinical data presented at the 2020 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s Annual Meeting and the 2019 and 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meetings support the development of JTX-8064 as a novel immunotherapy to reprogram immune-suppressive macrophages and enhance anti-tumor immunity. A Phase 1/2 clinical trial named INNATE (NCT04669899) of JTX-8064 as a monotherapy and in combination with Jounce’s internal anti-PD-1 inhibitor, pimivalimab (formerly JTX-4014) is currently enrolling patients with advanced solid tumors.

About Vopratelimab

Vopratelimab is a clinical-stage monoclonal antibody that binds to and activates ICOS, the Inducible T cell CO-Stimulator, a protein on the surface of certain T cells commonly found in many solid tumors. Vopratelimab is being assessed in the SELECT Phase 2 clinical trial (NCT04549025) in combination with Jounce’s internal investigational PD-1 inhibitor, pimivalimab (formerly JTX-4014), compared to pimivalimab alone. The SELECT trial completed enrollment of 69 immunotherapy naïve NSCLC patients who have been pre-selected with the TISvopra predictive biomarker, an 18 gene RNA tumor inflammation signature which predicted the emergence of ICOS hi CD4 T cells and clinical benefit in the ICONIC trial of vopratelimab alone and in combination with a PD-1 inhibitor.

About Pimivalimab

Pimivalimab (formerly JTX-4014) is a well-characterized fully human IgG4 monoclonal antibody designed to block binding to PD-L1 and PD-L2. Pimivalimab demonstrated a 17% durable overall response rate in a Phase 1 trial of 18 heavily pre-treated PD-(L)1 inhibitor naïve patients, which excluded all tumor types for which PD-(L)1 inhibitors were approved. In this Phase 1 trial, pimivalimab was shown to have an acceptable safety profile. Pimivalimab is currently being assessed in the INNATE Phase 1/2 trial (NCT04669899) in combination with JTX-8064, a LILRB2 (ILT4) inhibitor. Pimivalimab is also being assessed in the SELECT Phase 2 clinical trial (NCT04549025) in combination with vopratelimab.

On December 8, 2022 RAPT Therapeutics, Inc. (Nasdaq: RAPT), a clinical-stage, immunology-based biopharmaceutical company focused on discovering, developing and commercializing oral small molecule therapies for patients with significant unmet needs in inflammatory diseases and oncology, reported a poster presentation at the ESMO (Free ESMO Whitepaper) IO Congress covering data from its ongoing Phase 1/2 clinical trial of FLX475 as monotherapy and in combination with pembrolizumab in patients with advanced cancer (NCT03674567) (Press release, RAPT Therapeutics, DEC 8, 2022, https://investors.rapt.com/news-releases/news-release-details/rapt-therapeutics-presents-update-its-phase-12-clinical-trial [SID1234624924]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The data showed a confirmed overall response rate of 31% (4/13 patients) in Stage 1 of a Phase 2 expansion cohort of patients with checkpoint-naïve NSCLC, including two responses which are ongoing for over one year. Of the 13 patients treated with 100 mg once-daily FLX475 and a standard regimen of pembrolizumab, eight patients had PD-L1 positive tumors (TPS ≥1%), including two with PD-L1 high tumors (TPS ≥50%), four patients had PD-L1 negative tumors (TPS <1%) and one patient’s PD-L1 status was unknown. The confirmed response rate in the PD-L1 positive tumors was 38% (3/8 patients) and in the PD-L1 negative tumors was 25% (1/4 patients). None of the four responders were PD-L1 high. Most of the patients enrolled in this NSCLC cohort had been previously treated with 1-3 or more prior therapies for advanced disease (10/13 patients).

In a separate Phase 2 expansion cohort of six patients with EBV+ NK/T cell lymphoma treated with FLX475 monotherapy, there were four responses, with two durable complete metabolic responses (CMR), one unconfirmed CMR and one unconfirmed partial metabolic response.

The safety profile for FLX475 was favorable, consistent with that previously seen in healthy volunteers, and there was no evidence of increased severity or frequency of adverse events in combination therapy compared to either FLX475 or pembrolizumab monotherapy.

"These data further support the antitumor activity for FLX475 with clear demonstration as a monotherapy and encouraging activity in a combination regimen with checkpoint inhibition," said Brian Wong, M.D., Ph.D., President and Chief Executive Officer of RAPT Therapeutics. "These data meet our criteria for continued development and based on the promising activity of FLX475 with pembrolizumab in checkpoint-naïve NSCLC patients, we have moved this indication to Stage 2 and are enrolling additional patients into the cohort."

About FLX475
FLX475 is a small molecule CCR4 antagonist designed to block the migration of regulatory T cells (Treg) specifically into tumors, but not healthy tissues. Treg represent a dominant pathway for downregulating the immune response, generally correlate with poor clinical outcomes, and may limit the effectiveness of currently available therapies such as checkpoint inhibitors. RAPT is developing FLX475 in "charged" tumors, which represent cancer types the company believes are most likely to respond to FLX475, where a large quantity of Treg cells are likely to be the cause of immune suppression within the tumor. FLX475 may restore naturally occurring antitumor immunity alone and may synergize with a variety of both conventional and immune-based therapies, such as radiation, chemotherapy, checkpoint inhibitors, immune stimulators, cancer vaccines, and adoptive T cell therapy.