On October 15, 2024 Lantern Pharma Inc. (NASDAQ: LTRN), an artificial intelligence (AI) company dedicated to developing cancer therapies and transforming the cost, pace, and timeline of oncology drug discovery and development, reported that the FDA has granted Fast Track Designation for investigational drug candidate, LP-184, for treatment of Glioblastoma (Press release, Lantern Pharma, OCT 15, 2024, View Source [SID1234647216]). LP-184 is currently in a Phase 1A clinical trial designed to evaluate the safety and tolerability of the synthetically lethal investigational drug candidate in a broad range of solid tumors, including Glioblastoma (GBM). LP-184 was optimized and advanced in part with Lantern’s AI platform, RADR, to aid in the validation of mechanisms that could be exploited in the clinical setting to eradicate challenging cancers, and uncover insights in targeted patient populations. RADR is Lantern’s AI platform for cancer therapy discovery, development and rescue with over 100 billion data points and aiding in the development of both Lantern’s portfolio and development initiatives with Lantern’s collaborators.

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About GBM and the need for improved and novel therapies.

Glioblastoma (GBM) affects nearly 13,000 patients annually in the US and approximately 300,000 globally, with a mortality rate of 94%. Current standard of care therapies result in a life expectancy in GBM patients of less than 15 months. A major limitation to development of new drugs in the treatment of GBM is the need for potential drugs to have the ability to cross the blood brain barrier (BBB) as well as the ability to counteract the inherent and adaptive resistance of GBM cancer cells to temozolomide, the current standard of care in GBM. This resistance is largely derived from the expression of the DNA repair enzyme MGMT1. LP-184 activity is agnostic to MGMT expression, meaning it does not depend on the under or over-expression of MGMT in GBM and has shown in-vivo, preclinical activity in both types of GBM models.

No new drugs for GBM have been approved in over two decades. Lantern Pharma is advancing LP-184, a molecule which demonstrates synthetic lethality when combined with agents that cause DNA damage repair deficiency.2 Additionally, LP-184 has shown that it causes double-stranded breaks in the DNA of recurrent GBM (rGBM) cancer cells in multiple in-vivo models and is currently being advanced in early clinical stage studies.

"Receiving FDA Fast Track Designation for Lantern Pharma’s LP-184 in GBM reinforces our belief that this drug-candidate can help in the critical need to find effective treatment options for patients with GBM and further supports the potential of LP-184 to address the challenges in aggressive CNS cancers, where patients have a critical need for novel and life extending therapies" said Panna Sharma, President and CEO of Lantern Pharma.

Current status of LP-184 & STAR-001 in clinical trials & development

LP-184 is currently being studied in a phase 1A clinical trial to evaluate the safety, tolerability and maximum tolerated dose (MTD) of the potential therapy in a wide range of tumors, including GBM. The full study design can be viewed here (clinicaltrials.gov). Once the MTD has been established, Lantern has plans to advance the drug-candidate LP-184 as STAR-001 through its wholly owned subsidiary, Starlight Therapeutics, in GBM and other CNS and brain cancers.

Lantern also anticipates further using RADR to determine potential additional suitability for LP-184 in combination with other approved agents for the control of cancer progression in multiple other patient subgroups. Lantern has provided information on the development of LP-184 in GBM and has also discussed its plan to advance STAR-001 (LP-184 for CNS cancers) in multiple publicly available webinars, including on:

June 26, 2024 — STAR-001 in Multiple Brain and CNS Cancers with Dr. Marc Chamberlain, and
July 31, 2024 — Born from AI, Lighting The Way in CNS Cancer Treatment with Mr. Panna Sharma.
The proposed goals for the development of Phase 1b/2a clinical studies are targeting a rGBM specific trial to begin in late 2024 or early 2025. This trial is being planned to assess LP-184 in a Phase 1b/2a study as mono-therapy and in combination with spironolactone in rGBM to assess safety, pharmacokinetics and preliminary efficacy. Concurrently, Lantern will conduct a retrospective correlative analysis of multiple key markers of DNA damage as exploratory endpoints. EGFR expression or mutation status, MGMT status and expression of DNA damage repair pathway are also planned to be studied as potential response predictors to help inform and guide future late-stage trials and to stratify enrollment.

About the FDA Fast Track process

The FDA’s Fast Track process is designed to facilitate development and expedite the review of therapies intended to treat serious conditions and address unmet medical needs to potentially bring important new medicines to patients sooner. Companies whose programs are granted Fast Track Designation are eligible for more frequent interactions with the FDA during clinical development. For more information on Fast Track designation, please visit the FDA’s website at www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track.

On October 15, 2024 Novocure (NASDAQ: NVCR) reported that the U.S. Food and Drug Administration (FDA) has approved Optune Lua for concurrent use with PD-1/PD-L1 inhibitors or docetaxel, for the treatment of adult patients with metastatic non-small cell lung cancer (mNSCLC) who have progressed on or after a platinum-based regimen (Press release, NovoCure, OCT 15, 2024, View Source [SID1234647215]).

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"Novocure is committed to extending survival in some of the most aggressive and difficult to treat cancers. The approval of Optune Lua brings a new and urgently needed option for people with metastatic NSCLC who have progressed while on or after platinum-based chemotherapy," said Asaf Danziger, CEO, Novocure. "We are grateful to the patients, caregivers, investigators and healthcare providers who supported the clinical trials that led to this approval."

Optune Lua is a portable device that produces alternating electric fields known as tumor treating fields (TTFields), which are delivered through non-invasive, wearable arrays. TTFields exert physical forces on the electrically charged components of dividing cancer cells, resulting in cell death.

"There have been a number of important advances in first-line treatment for NSCLC, but this is an aggressive disease, and most patients will develop progression, with limited effective treatment options in second line and beyond," said Ticiana Leal, MD, Associate Professor and Director of the Thoracic Oncology Program at the Winship Cancer Institute of Emory University School of Medicine and primary investigator of the LUNAR study. "The overall survival results we observed with Optune Lua in the LUNAR study mark the first substantial improvement in more than 8 years in this patient population which, when combined with Optune Lua’s lack of systemic toxicity, make this a compelling development for many patients and their physicians who need better treatment options for this advanced disease."

"We are excited patients with metastatic NSCLC have more options, which they urgently need," said GO2 for Lung Cancer Chief Patient Officer Danielle Hicks. "The fight against lung cancer is always evolving, and the number of people affected by this disease is underappreciated. That is why Novocure’s commitment to advancing treatment is exciting for the whole lung cancer community."

Data Supporting the Optune Lua Approval

The Phase 3 LUNAR study was a prospective, randomized, open-label, multicenter study that compared the use of Optune Lua concurrent with PD-1/PD-L1 inhibitors or docetaxel (experimental arm) to PD-1/PD-L1 inhibitors or docetaxel alone (control arm) for patients with metastatic NSCLC who progressed during or after platinum-based therapy.

The primary endpoint of the study was achieved demonstrating a statistically significant and clinically meaningful 3.3-month (P=0.04) extension in median overall survival (OS) for patients treated with Optune Lua concurrently with a PD-1/PD-L1 inhibitor or docetaxel (n=145). The group treated with Optune Lua concurrently with a PD-1/PD-L1 inhibitor or docetaxel had a median OS of 13.2 months (95% CI, 10.3 to 15.5 months) compared to a median OS of 9.9 months (95% CI, 8.2 to 12.2 months) in the PD-1/PD-L1 inhibitor or docetaxel treated group (n=146).

The LUNAR study included two pre-specified powered secondary endpoints. The first secondary endpoint, which met statistical significance, assessed median OS in patients treated with Optune Lua concurrently with a PD-1/PD-L1 inhibitor versus a PD-1/PD-L1 inhibitor alone. The second secondary endpoint, which showed a positive trend but did not meet statistical significance, assessed Optune Lua concurrently with docetaxel versus docetaxel alone.

Patients randomized to Optune Lua and a PD-1/PD-L1 inhibitor (n=70) demonstrated a median OS of 19.0 months (95% CI, 10.6 to 28.2 months) compared to a median OS of 10.8 months (95% CI, 8.3 to 17.6 months) in patients treated a with PD-1/PD-L1 inhibitor alone (n=71), which was a statistically significant extension in median OS of more than 8.0 months (P=0.02).

Patients randomized to receive Optune Lua and docetaxel (n=75) had a median OS of 11.1 months (95% CI, 8.2 to 13.9 months) compared to a median OS of 8.9 months (95% CI, 6.5 to 11.3 months) in patients treated with docetaxel alone (n=75). This 2.2 month extension in median OS did not provide a statistically significant demonstrated benefit, but did show a positive trend.

Device-related adverse events (AEs) occurred in 63.1% of patients (n=89), these were skin-related disorders under the transducer arrays. The majority of these events were low grade (Grade 1 – 2), with only 4% (n=6) experiencing Grade 3 skin toxicity that required a break from treatment. There were no Grade 4 or Grade 5 toxicities related to Optune Lua, and no device-related AEs that caused death.

Baseline patient characteristics were well balanced between cohorts: median age was 65 years (range, 22-86); 66% male, 34% female; 96% of patients had an ECOG performance status of 0-1. PD-L1 expression data were collected from 83% of patients (69 of 83 patients) enrolled at U.S. sites and were well balanced across the four cohorts.

Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the most common cause of cancer-related death worldwide1, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. It is estimated that approximately 193,000 patients are diagnosed with NSCLC each year in the U.S.

Physicians use different combinations of surgery, radiation and pharmacological therapies to treat NSCLC, depending on the stage of the disease. Surgery, which may be curative in a subset of patients, is usually used in early stages of the disease. Since 1991, radiation with a combination of platinum-based chemotherapy drugs has been the first-line standard of care for locally advanced or metastatic NSCLC. Certain immune checkpoint inhibitors, including both PD-1 and PD-L1 inhibitors, have been approved for the first-line treatment of NSCLC and the standard of care in this setting continues to evolve rapidly.

It is estimated that approximately 30,000 patients actively seek treatment for stage 4 NSCLC after progressing during or after platinum-based therapy each year in the U.S. The standard of care for second-line treatment is also evolving and may include platinum-based chemotherapy for patients who received immune checkpoint inhibitors as their first-line regimen, pemetrexed, docetaxel or immune checkpoint inhibitors.

What is Optune Lua approved to treat?

Optune Lua is a wearable, portable, FDA-approved device used together with PD-1/PD-L1 inhibitors (immunotherapy) or docetaxel. It is indicated for adult patients with metastatic non-small cell lung cancer (mNSCLC) who have progressed on or after a platinum-based regimen.

Important Safety Information

Who should not use Optune Lua?

Optune Lua for mNSCLC is not for everyone. Talk to your doctor if you have:

An electrical implant. Use of Optune Lua together with electrical implants has not been tested and may cause the implanted device not to work properly
A known sensitivity to gels like the gel used on electrocardiogram (ECG) stickers or transcutaneous electrical nerve stimulation (TENS) electrodes. In this case, skin contact with the gel used with Optune Lua may commonly cause increased redness and itching, and rarely may even lead to severe allergies such as a fall in blood pressure and difficulty breathing
Do not use Optune Lua if you are pregnant or are planning to become pregnant. It is not known if Optune Lua is safe or effective during pregnancy.

What should I know before using Optune Lua?

Optune Lua should only be used after receiving training from qualified personnel, such as your doctor, a nurse, or other medical staff who have completed a training course given by Novocure, the maker of Optune Lua.

Do not use any parts that did not come with Optune Lua Treatment Kit sent to you by Novocure or given to you by your doctor
Do not get the device or transducer arrays wet
Please be aware that Optune Lua has a cord that plugs into an electrical socket. Be careful of tripping when it’s connected
If you have an underlying serious skin condition where the transducer arrays are placed, discuss with your doctor whether this may prevent or temporarily interfere with Optune Lua treatment
What are the possible side effects of Optune Lua?

The most common side effects of Optune Lua when used together with certain immunotherapy and chemotherapy drugs were dermatitis, pain in the muscles, bones, or joints, fatigue, anemia, alopecia (hair loss), dyspnea, nausea, cough, diarrhea, anorexia, pruritus (itching), leukopenia, pneumonia, respiratory tract infection, localized edema (swelling), rash, pain, constipation, skin ulcers, hypokalemia (low potassium levels), hypoalbuminemia (low albumin levels), hyponatremia (low sodium levels), and dysphagia (difficulty swallowing).

Other potential adverse effects associated with the use of Optune Lua include treatment related skin irritation, allergic reaction to the adhesive or to the gel, overheating of the array leading to pain and/or local skin burns, infections at site where the arrays make contact with the skin, local warmth and tingling sensation beneath the arrays, medical device site reaction, muscle twitching, and skin breakdown/skin ulcer. Talk to your doctor if you have any of these side effects or questions.

About Tumor Treating Fields

Tumor Treating Fields (TTFields) are electric fields that exert physical forces to kill cancer cells via a variety of mechanisms. TTFields do not significantly affect healthy cells because they have different properties (including division rate, morphology, and electrical properties) than cancer cells. These multiple, distinct mechanisms work together to target and kill cancer cells. Due to these multimechanistic actions, TTFields therapy can be added to cancer treatment modalities in approved indications and demonstrates enhanced effects across solid tumor types when used with chemotherapy, radiotherapy, immune checkpoint inhibition, or targeted therapies in preclinical models. TTFields therapy provides clinical versatility that has the potential to help address treatment challenges across a range of solid tumors.

On October 15, 2024 Lomond Therapeutics, a subsidiary of Eilean Therapeutics LLC, a biopharmaceutical company dedicated to discovering and developing best-in-class and first-in-class small molecule inhibitors to target escape mutations in hematologic and solid malignancies, reported that the U.S. Food and Drug Administration (FDA) has cleared Lomond’s Investigational New Drug (IND) application for a Phase 1 multicenter study evaluating the feasibility, safety, and efficacy of lonitoclax in patients with relapsed/refractory chronic lymphocytic leukemia, small lymphocytic lymphoma, and select low-grade lymphomas (Press release, Lomond Therapeutics, OCT 15, 2024, View Source [SID1234647214]).

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"We are pleased with the progress we have made to date and excited with the FDA clearance of our IND to initiate patient testing of lonitoclax," said Dr. Iain Dukes, Chief Executive Officer of Eilean Therapeutics. "Given the highly differentiated pre-clinical and healthy volunteer profile of lonitoclax, we believe that lonitoclax has the potential to be the best-in-class BCL-2 inhibitor and look forward to working with the leukemia and lymphoma community in initiating our Phase 1 clinical study."

About Lonitoclax

Lonitoclax has earlier reported novel binding, best-in-class potency and selectivity against BCL-2, a key pro-survival protein that is overexpressed in many cancers. This clinical candidate demonstrated equivalent in vivo anti-tumor efficacy to venetoclax in B cell and myeloid malignancy cell lines and in vivo models. Compared to venetoclax, lonitoclax exhibits significantly less suppression of non-malignant immune cell populations, a result that suggests superior selectivity, and an improved safety profile. Lonitoclax has previously completed a series of healthy volunteer studies where no safety signals were observed at exposures where ex vivo activation of caspase in CLL primary cells was observed, a surrogate marker of BCL-2 inhibition in tumors. This emphasizes important advantages over venetoclax and venetoclax-like molecules in safety, tolerability, and feasibility of outpatient treatment, enabling the molecule to safely target AML and CLL patients alone and in combination with other targeted therapies.

On October 15, 2024 Lutris Pharma, a clinical stage biopharmaceutical company focused on improving anti-cancer therapies by reducing cutaneous dose limiting toxicity, reported that it has completed enrollment in the phase 2 trial of lead compound, LUT014, a topically-applied novel B-Raf inhibitor, for patients with metastatic colorectal cancer (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitor therapy who develop dose-limiting acneiform rash (Press release, Lutris Pharma, OCT 15, 2024, View Source [SID1234647213]). Topline results are expected in first quarter of2025.

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The phase 2, randomized, double-blind, placebo-controlled trial has enrolled a total of 117 subjects at 20 international sites, including Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center and Dana Farber Cancer Institute. The trial is evaluating the efficacy and safety of two strengths of LUT014 gel, 0.03% or 0.10%, applied once daily for 4 weeks, compared to placebo (with a randomization of 1:1:1), in patients with mCRC who develop Grade 2 or non-infected Grade 3 EGFR inhibitor-induced acneiform rash, with a 4-week follow up period. During an optional open label extension period for the placebo group, eligible subjects received the 0.03% concentration of LUT014.

The study’s primary endpoint is the proportion of subjects in each treatment group who achieve treatment success, defined as an improvement (decrease) of at least one grade in the severity of the acneiform lesions from baseline to Day 28, based on common terminology criteria for adverse events (CTCAE) V5.0 skin and subcutaneous tissue disorders grading scale or, an improvement (increase) of at least 5 points in the total score for the skin-specific (first 13 questions) of the functional assessment of cancer therapy epidermal growth factor receptor inhibitor 18 (FACT-EGFRI-18) health related quality of life (HRQoL) questionnaire, from baseline to Day 28. Key secondary endpoints include adherence to EGFR inhibitor treatment.

"Enrollment of the last patient is an important milestone for Lutris Pharma and in the progress of the international phase 2 trial of LUT014," stated Antoni Ribas, M.D., Ph.D., Chairman and Founder of Lutris Pharma. "Although EGFR inhibitors are critical treatment options, approximately 75% of patients with mCRC receiving such therapy experience acneiform rash, which can be so disruptive to quality of life that many of these patients do not receive the optimal treatment against their cancer, either due to dose reduction or even discontinuation of the anti-EGFR therapy, caused by the rash. By reversing the inhibitory effect of anti-EGFR therapy on downstream signaling in the skin cells, we believe that LUT014 has the potential to address a toxicity of otherwise effective therapeutic regimens and can have a favorable impact for patients who currently have no other treatment options.

Dr. Ribas continued, "having generated positive phase 1 results in patients with mCRC, demonstrating safety, preliminary efficacy a dose response and a therapeutic benefit in all patients, we look forward to reporting topline results from the phase 2 study early next year and are planning present them at a major medical meeting."

"Reporting data on the use of LUT014 to treat acneiform rash induced by anti-EGFR inhibitors will be timely, given the encouraging data generated with new classes of EGFR inhibitors being developed for the treatment of cancer" added Noa Shelach, Ph.D., Chief Executive Officer of Lutris Pharma. "These active anticancer agents have the same class-effect dose limiting skin toxicities that could be addressed with the topical application of LUT014, potentially broadening the clinical benefit to patients with cancer."

For more information on this clinical trial, please visit: www.clinicaltrials.gov, NCT04759664.

About EGFR Inhibitor-Induced Rash
EGFR is a receptor on the surface of cells which is expressed in many normal epithelial tissues, including skin. The EGFR signaling pathway is one of the key pathways that regulate growth, survival, proliferation, and differentiation of cells. B-Raf is a protein encoded by the BRAF gene and is a downstream effector component of EGFR signaling pathway. EGFR has been shown to be over-activated in various human cancers, including colorectal, lung, head and neck, urinary bladder, pancreatic and breast cancers, eliciting downstream phosphorylation and activation of the MAP Kinase pathway.

Drugs called EGFR inhibitors can block the EGFR signal responsible for cell growth. Among the various types of pharmacological therapies for cancer, EGFR inhibitors are increasingly being used both as primary therapy as well as in patients who have failed prior chemotherapy. Although effective as anti-cancer therapy leading to tumor shrinkage, EGFR inhibitors have many adverse reactions associated with their use. The majority of patients treated with EGFR inhibitors will experience adverse dermatological side effects typically manifested as a papulopustular skin rash, also known as acneiform lesions, which can impact quality of life and affect adherence to therapy.

About LUT014
LUT014 is a novel B-Raf inhibitor which is applied topically on the skin. When the B-Raf protein is mutated, as is the case in some human cancers such as melanoma, blocking this pathway leads to apoptosis of the cells and tumor shrinkage. However, when the same pathway is blocked in normal, non-mutated cells, the opposite happens: the MAPK pathway is activated, and cells start growing. This phenomenon is recognized as the paradoxical effect of B-Raf Inhibitors. LUT014 harnesses the paradoxical effect of B-Raf Inhibitors in order to enhance cell proliferation and balance cell destruction, typical to radiation dermatitis.

On October 15, 2024 Triumvira Immunologics, a clinical-stage company developing novel, targeted autologous and allogeneic T cell therapeutics that co-opt the natural biology of T cells to treat patients with solid tumors, reported the publication of a peer-reviewed article titled "Preclinical development of T cells engineered to express a T cell antigen coupler (TAC) targeting Claudin 18.2-positive solid tumors" in Cancer Immunology Research, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Triumvira Immunologics, OCT 15, 2024, View Source [SID1234647212]). The article, authored by a team of scientists led by Dr. Andreas Bader, Triumvira’s Consulting Chief Scientific Officer, details the preclinical pharmacology and safety of TAC01-CLDN18.2, a novel autologous T cell therapy targeting Claudin 18.2 for the treatment of solid tumors. TAC01-CLDN18.2 is currently the subject of a clinical Phase I/II study (TACTIC-3, NCT05862324).

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"Our findings highlight the unique advantages of TAC01-CLDN18.2, which is designed to target and eliminate tumors with high specificity while minimizing the risk of adverse events that are commonly associated with T cell and other therapies," said Andreas Bader, Ph.D., Consulting Chief Scientific Officer of Triumvira Immunologics. "This research underscores our commitment to developing next-generation T cell therapies that are both effective and safe, and we are excited to continue exploring the clinical potential of TAC01-CLDN18.2 in treating patients with Claudin 18.2 positive solid tumors."

"Publishing this research is a significant milestone for Triumvira, as it reinforces the potential of our TAC technology, currently in the clinic for Claudin 18.2 positive tumors, to transform the treatment landscape for cancer patients," said Robert Williamson, President of Triumvira Immunologics. "We remain committed to bringing innovative, life-saving treatments to patients in need, and this publication is a testament to the rigorous science in the company and dedication of our team."

The study highlights the novel and proprietary T cell Antigen Coupler (TAC) technology from Triumvira Immunologics, a chimeric receptor that promotes tumor antigen-specific activation of T cells by leveraging the natural T cell receptor complex without causing tonic signaling. The preclinical results demonstrate that CLDN18.2-TAC T cells exhibit specific and durable anti-tumor activity across various in vitro and in vivo models of gastric, gastroesophageal, and pancreatic cancers. Importantly, the study reports high selectivity as these T cells did not induce notable off-target or on-target/off-tumor toxicities in these preclinical models, suggesting its potential safety and efficacy in clinical settings.

Key Findings

Specificity and Activity: TAC01-CLDN18.2 T cells demonstrated high specificity and potent cytotoxicity against Claudin 18.2 positive tumor cells in both 2D cultures and 3D tumor spheroids, including models with low antigen expression.
CLDN18.2-TAC T vs CLDN18.2 CAR-T: In a head-to-head comparison against CLDN18.2-directed 2nd-generation CAR T cells, CLDN18.2-TAC T cells exhibited greater proliferative capacity, lower levels and delayed onset of T cell exhaustion, and overall greater and longer-lasting cytotoxicity in a recursive tumor cell killing assay.
In Vivo Efficacy: In mouse models of gastric, gastroesophageal, and pancreatic cancers, TAC01-CLDN18.2 T cells effectively eradicated tumor xenografts, with durable efficacy observed in recursive killing and tumor rechallenge experiments.
Safety Profile: The preclinical data showed that TAC01-CLDN18.2 T cells did not induce notable off-target or on-target/off-tumor toxicities, as these cells were unreactive to human cells representing vital organs.
Durable Response: The research indicates that TAC01-CLDN18.2 T cells can induce a long-lasting anti-tumor response, supporting their potential as a safe and effective treatment for patients with Claudin 18.2 positive solid tumors.
Full Publication Details

Title: Preclinical development of T cells engineered to express a T cell antigen coupler (TAC) targeting Claudin 18.2-positive solid tumors
Journal: Cancer Immunology Research
Corresponding Authors: Andreas Bader, Ph.D., Christopher Helsen, Ph.D.
Full Author List: Stacey Xu, Ling Wang, Philbert Ip, Ritu Randhawa, Tania Benatar, Suzanna Prosser, Prabha Lal, Alima Khan, Thanyashanthi Nitya-Nootan, Gargi Thakor, Heather MacGregor, Danielle Hayes, Andrea Vucicevic, Princy Mathew, Sadhak Sengupta, Christopher Helsen, and Andreas Bader