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Bio4t2 announces trial evaluating repeat infusions of CAR-T targeting solid tumors without lymphodepletion

On October 17, 2023 Bio4t2 reported to have received regulatory approvals to repeatedly administer patients with T cells engineered to express a chimeric antigen receptor (CAR) targeting BT-001, an antigen on solid tumors identified using the PrismCore platform (Press release, Bio4T2, OCT 17, 2023, View Source [SID1234636085]). The CAR-T, termed B4t2-001, are predicted to engraft without preparative chemotherapy (lymphodepletion) based on the Bio-Engine technology enabling multiple infusions for each recipient to further improve the therapeutic effect.

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Clinical trial repeatedly infuses CAR-T without lymphodepletion to treat solid tumors.

Bio4t2, global clinical stage biopharmaceutical company combines PrismCore and Bio-Engine technologies to advance cutting-edge CAR-T therapy in phase 1 clinical trial.
Bio4t2, global clinical stage biopharmaceutical company combines PrismCore and Bio-Engine technologies to advance cutting-edge CAR-T therapy in phase 1 clinical trial.
The PrismCore platform generates CAR-T that recognizes overexpressed self-antigens on solid tumors. Bio-Engine adapts the CAR-T to transiently recognize a subset of circulating blood cells to boost the numbers of infused genetically modified T cells without the need for preparative chemotherapy. Bio4t2 harnesses these technologies to unlock the commercial potential of CAR-T in patients with invasive cancers.

A prior pilot investigator-initiated trial (clinicaltrials.gov NCT05621486) demonstrated that B4t2-001 can engraft to the range of 40 to 50% of circulating lymphocytes, even when lymphodepletion was omitted, and resulted in anti-tumor effects.

"This new phase 1 trial builds off our pilot clinical study which concluded a few weeks ago," said Dr. Laurence Cooper MD-PhD, Executive Chairman of the board. "Treating solid tumors depends on identifying targets that are uniformly expressed across cancer cells and engrafting CAR-T without immunological exhaustion. We combine our PrismCore and Bio-Engine technologies to achieve both goals and advance our cutting-edge CAR-T for the many patients with solid tumors," added Dr. Cooper.

"PrismCore identifies targets on invasive cancers and Bio-Engine harnesses normal blood cells to create a niche for CAR-T engraftment without the use of preparative chemotherapy," said Farzad Haerizadeh, PhD, Chief Scientific Officer, and co-founder. "Based on the success of our pilot clinical study, Bio4t2’s CAR-T is predicted to attack the tumor again and again without the cost, complexity, and toxicities, associated with lymphodepletion," said Haerizadeh.

About the clinical trial

The phase 1 investigator-initiated study (clinicals.gov NCT06072989) evaluates intra-patient repeat administration and inter-patient ascending doses of B4t2-001 targeting BT-001 without lymphodepletion in adult patients with solid tumors at Shanghai East and Shanghai Artemed hospitals in the People’s Republic of China. Furthermore, this trial assesses the safety, tolerability, pharmacokinetic, pharmacodynamic, and preliminary efficacy of autologous CAR-T.

Mirati Presents Late-Breaking Results Evaluating the Combination of Adagrasib and Pembrolizumab in First-Line Non-Small Cell Lung Cancer (NSCLC)

On October 17, 2023 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a commercial stage biotechnology company, reported updated results from the KRYSTAL-7 Phase 2 study evaluating adagrasib combined with pembrolizumab in patients for the treatment of first-line NSCLC harboring a KRASG12C mutation at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (ESMO) (Free ESMO Whitepaper) 2023 (Press release, Mirati, OCT 17, 2023, View Source [SID1234636084]). These data demonstrate a manageable safety profile and early signs of durability of adagrasib in combination with a checkpoint inhibitor in the first-line NSCLC setting.

Summary of Clinical Results

In patients with PD-L1 TPS ≥50%, adagrasib and pembrolizumab demonstrated an overall response rate (ORR) of 63% and disease control rate (DCR) of 84% and promising early signs of durability. The 63% confirmed response rate compares favorably to pembrolizumab monotherapy which has demonstrated an ORR of 39-45%.1,2
A median progression free survival has not been reached at 10.1 months median follow up.
The safety profile of the adagrasib and pembrolizumab combination was consistent with either agent as monotherapy, with a low rate of treatment related adverse events (TRAEs) leading to discontinuation of both drugs in only 4% of patients.
Treatment related hepatic events occurred in <10% of patients and were predominantly low grade. No patients discontinued both adagrasib and pembrolizumab due to ALT/AST increase or hepatic-related TRAEs.
"Data presented to date indicate that adagrasib prescribed following or in combination with immunotherapy offers a tolerable safety regimen for first-line NSCLC patients with a KRASG12C mutation," said Marina C. Garassino, M.D., professor of medicine, UChicago Medicine. "Adagrasib is the only KRASG12C inhibitor to be feasibly combined concurrently or following immunotherapy with a well-managed hepatoxicity profile, and still exhibits positive efficacy signals."

"We are pleased to see these significant findings, which further support the initiation of a global Phase 3 study evaluating the combination of adagrasib plus immunotherapy in the first-line setting for KRASG12C-mutated NSCLC with PD-L1 TPS ≥50% for the benefit of patients," said Alan Sandler, M.D., chief medical officer, Mirati Therapeutics. "Potential combinability with an immunotherapy, in addition to encouraging clinical activity in other tumor types and demonstrated central nervous system (CNS) penetration, reinforces our confidence in the differentiation of adagrasib from other potential treatment options and the benefit it offers to patients."

Mirati plans to initiate a Phase 3 clinical study to evaluate adagrasib in combination with pembrolizumab in the first line setting for KRASG12C-mutated NSCLC with PD-L1 TPS ≥50%. Initial patient enrollment is expected by year-end 2023.

First Patient Dosed in the Registrational Phase III Study of Olverembatinib in Treatment-Naïve Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

On October 17, 2023 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, chronic hepatitis B (CHB), and age-related diseases, reported that the registrational Phase III study (HQP1351AG301, NCT06051409) of olverembatinib, Ascentage Pharma’s lead drug candidate, combined with chemotherapy, versus imatinib combined with chemotherapy in treatment-naïve patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has dosed its first patient (Press release, Ascentage Pharma, OCT 17, 2023, View Source [SID1234636083]). As a global best-in-class drug, olverembatinib holds the promise of becoming the first tyrosine kinase inhibitor (TKI) approved in China for the first-line treatment of Ph+ ALL.

This global multi-center, randomized-controlled, open-label, registrational Phase III study (HQP1351AG301) is designed to evaluate the efficacy and safety of olverembatinib combined with chemotherapy versus imatinib combined with chemotherapy in newly-diagnosed patients with Ph+ ALL.

Accounting for 20%-30% of all ALL cases in adults, Ph+ ALL is commonly associated with a high relapse rate, short progression-free survival, and poor prognosis. Prior to the introduction of TKIs, a class of targeted small molecule compounds, allogeneic hematopoietic stem cell transplantation (allo-HSCT) after achieving complete responses (CRs) from chemotherapy was widely adopted as a first-line treatment for patients with Ph+ ALL. However, the five-year overall survival (OS) was only less than 30% and more than 70% patients relapsed before the transplantation or simply lacked access to the surgical treatment[1].

The clinical adoption of TKIs has resulted in a new clinical paradigm for patients with Ph+ ALL. However, first and second-generation TKIs have known clinical limitations, including high relapse rates and disappointing long-term survival with a three to five-year OS rate of just about 50%[2]. These limitations are primarily caused by low complete molecular responses (CMRs) and T315I kinase domain mutations, thus leaving substantial room for improvement in the treatment of Ph+ ALL. Currently, no TKI has been approved for the first-line treatment of Ph+ ALL in China and third-generation TKIs with more potent efficacy can potentially provide better prognosis to patients with Ph+ ALL by inducing a higher rate of CMRs and inhibiting the T315I mutation.

Ascentage Pharma’s novel drug candidate, olverembatinib, is an orally-administered third-generation TKI and the first and only China-approved third-generation BCR-ABL inhibitor. Currently, olverembatinib is being jointly commercialized by Ascentage Pharma and Innovent Biologics. In November 2021, Olverembatinib was approved by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) for the treatment of adult patients with TKI-resistant chronic-phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation. Previously, olverembatinib received a recommendation from the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment Hematologic Malignancies as a treatment option for patients with Ph+ ALL.

(Olverembatinib is an investigational drug that has not been approved for any indication outside the Chinese mainland)

Prof. Weili Zhao, Vice President of Shanghai Jiaotong University School of Medicine Affiliated Ruijin Hospital and Director of Shanghai Institute of Hematology, commented, "Ph+ ALL used to be the most high-risk and difficult-to-treat subtype of leukemia and the introduction of TKIs has resulted in improved prognosis to patients with this condition. However, clinicians face the pressing question of which TKI offers the best efficacy and safety. We hope HQP1351AG301, a clinical study evaluating olverembatinib, a China-developed next-generation TKI, can provide an answer to those important questions."

Prof. Suning Chen, Deputy Director of the Hematology Department, the First Affiliated Hospital of Soochow University and Deputy Director of Jiangsu Institute of Hematology, noted, "Since its launch, olverembatinib showed excellent efficacy in patients with Ph+ ALL. We are very hopeful for the results from the HQP1351AG301 trial, as it is the first registrational clinical study for the first-line treatment of patients with Ph+ ALL."

Prof. Yang Shen, Deputy Director of the Hematology Department at Shanghai Jiaotong University School of Medicine Affiliated Ruijin Hospital, commented, "Olverembatinib has already been approved for the treatment of chronic myeloid leukemia in China. The HQP1351AG301 trial evaluates olverembatinib in Ph+ ALL, a potential additional indication in which olverembatinib has already showed promising therapeutic utility according to existing real-world data. We hope olverembatinib will offer a new treatment option to patients with Ph+ ALL."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "At present, the long-term survival rate of patients with Ph+ ALL remains disappointing, thus leaving considerable room for improvement. Multiple studies have shown that more potent third-generation TKIs can offer durable responses and a higher survival rate to patients with Ph+ ALL, yet no TKIs have been approved for the first-line setting in China. We are glad that this registrational Phase III study of olverembatinib, a TKI that could potentially become the first one approved in China for the first-line treatment of Ph+ ALL, has successfully enrolled and dosed its first patient. Moving forward, we will actively advance this clinical program and try to bring this drug to market as soon as possible for the benefit of more patients."

STORM Therapeutics Presented Novel Pre-Clinical Data on STC-15 at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics

On October 17, 2023 STORM Therapeutics Ltd. (STORM), a clinical stage biotechnology company discovering and developing novel small molecule therapies targeting RNA modifying enzymes (RMEs) for oncology and other diseases, reported that Dr. Yaara Ofir-Rosenfeld, Director of Translational Oncology at STORM, presented novel pre-clinical data investigating the combination of METTL3 inhibitors (METTL3i) with DNA damaging therapies at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in Boston, Massachusetts on the 11-15 October 2023 (Press release, STORM Therapeutics, OCT 17, 2023, View Source [SID1234636082]).

The presentation entitled "STC-15, a small molecule inhibitor of the RNA methyltransferase METTL3, activates anti-tumor immunity and reshapes the tumor microenvironment" detailed pre-clinical findings from STORM’s investigational drug STC-15 in combination with DNA damaging therapies. STC-15 is an orally bioavailable, highly selective METTL3 inhibitor and is the first molecule specifically targeting an RNA methyltransferase enzyme to enter clinical development.

STORM’s new data demonstrates that:

METTL3 inhibition enhances cytotoxicity of DNA damaging chemotherapies such as doxorubicin
Combination of STC-15 with chemotherapies activates cancer cell intrinsic interferon signalling that contributes to the induction of immunogenic cell death.
STC-15 synergises with radiation therapy in vivo
STC-15 reshapes the tumor microenvironment, shifting it from an immunosuppressive, pro-tumorigenic to an immune stimulatory, anti-tumor state
A first-in-human clinical trial on STORM’s lead clinical candidate STC-15 in patients with solid tumours is ongoing and can be found on clinicaltrials.gov under the identifier NCT05584111.

Yaara Ofir-Rosenfeld, Director of Translational Oncology of STORM Therapeutics, added, "Many tumours develop mechanisms that suppress their recognition by the immune system and limit their response to treatment. Our new findings reveal that STC-15 treatment shifts the tumour microenvironment to an immunostimulatory state and thereby boosts the efficacy of established cancer treatments such as radio- and chemotherapy."

Oliver Rausch, Chief Scientific Officer of STORM Therapeutics, commented, "These exciting new data build on our previous findings that STC-15 leads to activation of anti-tumor immunity and tumor killing. They illustrate a huge opportunity for STC-15 to be combined with a wide range of existing standard of care cancer drugs including checkpoint inhibitors and DNA damaging agents. This represents a major discovery for the STORM team as we look to develop STC-15 as a novel treatment option for cancer patients."

Details of the conference and presented abstract are as follow:

Abstract Title: STC-15, a small molecule inhibitor of the RNA methyltransferase METTL3, activates anti-tumor immunity and reshapes the tumor microenvironment

Presenter: Yaara Ofir-Rosenfeld1

Date and Time: Saturday, 14 October 2023, 12:30pm-4:00pm EDT

Location: Level 2, Exhibit Hall D

Poster number: C077

Session: Poster Session C

1STORM Therapeutics Ltd., Cambridge, UK

Beyond Cancer™ Publishes Pre-Clinical Data in Cells Demonstrating that the Combination of Ultra-High Concentration Nitric Oxide (UNO) and Anti-mPD-1 Therapy Improves Tumor Regression Rates and Survival in Mice

On October 17, 2023 Beyond Cancer, Ltd., an affiliate of Beyond Air, Inc. (NASDAQ: XAIR) that is developing ultra-high concentration nitric oxide (UNO) as an immunotherapeutic for solid tumors, reported the publication of pre-clinical data demonstrating that its proprietary technology reduces immunosuppression and creates a favorable microenvironment that can contribute to immune potentiation (Press release, Beyond Air, OCT 17, 2023, View Source [SID1234636081]).

The data were published in an article entitled, "Intratumoral Administration of High-Concentration Nitric Oxide and Anti-mPD-1 Treatment Improves Tumor Regression Rates and Survival in CT26 Tumor-Bearing Mice," in the peer-reviewed journal Cells. The article is available on the Cells website. (click here).

"The combination of UNO and anti-mPD-1 resulted in a potent, synergistic immune response," stated Dr. Hila Confino, Head of In Vivo Studies. "This work aligns with prior data utilizing UNO to treat solid tumors and has repeatedly demonstrated increased tumor regression rates and improvement in survival."

Dr. Frederick Dirbas, MD, Associate Professor of Surgery, Div of Surgical Oncology, Dept of Surgery, Stanford University School of Medicine and Chair of the Beyond Cancer Scientific Advisory Board commented, "This manuscript details the beneficial effects of UNO alone and in conjunction with immunotherapy in a murine tumor model. The boost seen with the combination of UNO and immunotherapy is important. We look forward to further investigation exploring mechanisms of action of UNO as well as the potential merits of UNO in treating human solid tumors."

The manuscript published in Cells describes several studies elucidating UNO’s effect on both the adaptive and innate immune responses, as well as tumor responses, to a single administration of therapy. Specifically, in vitro studies showed that PD-L1 was upregulated in both CT26 and 4T1 tumor models following exposure to UNO, implying a possible mechanism for overcoming PD-1 resistance (Figure 1).

PD-L1 Upregulation in CT26 and 4T1 Cells after In Vitro Exposure to UNO

Intratumorally, UNO resulted in a substantial and enduring reduction in the T-reg/CD8+ ratio demonstrating a less tumorigenic microenvironment (Figure 2).

T-cell profiling in tumors of CT26 mice treated with UNO

Systemically, the acute effects of UNO treatment included a decrease in MDSC’s and simultaneous increase in M1 macrophages, demonstrating a more immunogenic blood profile (Figure 3).

Myeloid cell profiling in CT26 tumors treated with UNO

Figure 3: Myeloid cell profiling in CT26 tumors treated with UNO

"The publication of our second peer-reviewed manuscript in the journal Cells further demonstrates the acceptance of the science of UNO by an expanding community of researchers," said Dr. Selena Chaisson, Chief Executive Officer. "I am excited for the presentation of our initial clinical data at SITC (Free SITC Whitepaper)."

About Nitric Oxide
Nitric Oxide (NO) is a potent molecule, naturally synthesized in the human body, proven to play a critical role in a broad array of biological functions. In the airways, NO targets the vascular smooth muscle cells that surround the small resistance arteries in the lungs. Currently, exogenous inhaled NO is used in adult respiratory distress syndrome, post certain cardiac surgeries and persistent pulmonary hypertension of the newborn to treat hypoxemia. Additionally, NO is believed to play a key role in the innate immune system and in vitro studies suggest that NO possesses anti-microbial activity not only against common bacteria, including both gram-positive and gram-negative, but also against other diverse pathogens.