On October 24, 2023 Imugene Limited (ASX: IMU), a clinical stage immuno-oncology company, reported that its B cell immunotherapy HER-Vaxx and CF33 oncolytic virotherapy CHECKVacc featured this week at the ESMO (Free ESMO Whitepaper) Congress, currently being held in Madrid 20-24 October 2023 (Press release, Immutep, OCT 24, 2023, View Source [SID1234636274]).

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The European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress is the most influential oncology platform for clinicians, researchers, patient advocates, journalists, and healthcare industry representatives from all over the world.

The presentation titles featuring Imugene’s HER-Vaxx and CHECKVacc are the following:

Poster 1536P: HERIZON: A Phase 2 study of HER-Vaxx (IMU-131), a HER2-targeting peptide vaccine plus standard of care chemotherapy in patients with HER2+ advanced stomach Cancer — dose-dependent anti-cancer antibodies correlating with improved clinical outcome. Presenter: Dr Joshua Tobias, Medical University of Vienna.

Highlights and conclusions
• As previously reported 27 June 2022 compared to chemotherapy alone, HER-Vaxx vaccination resulted in a statistically significant overall survival benefit.
• As previously reported at ESMO (Free ESMO Whitepaper) GI 30 June 2023 HER-Vaxx treatment produced statistically significant robust anti-HER2 antibody responses (p<0.0001).
• In this new presentation HER-Vaxx-based vaccination of patients with HER2-overexpressing gastric cancer validates the mechanism of action by demonstrating; (1) induced anti-HER2 antibody responses (p<0.001) with dose-dependent functionality in binding to human HER2-expressing gastric cancer cells, (2) intracellular phosphorylation inhibition of the HER2 receptor and (3) inhibiting the cancer signalling pathway kinases Akt and MAPK.
• The presented data further validate the proof of concept for the first-in-class Bcell immunotherapy HER-Vaxx.

Poster 472P: Prevention of metastasis formation by combination therapy targeting HER2 and PD-L1 in HER2-expressing tumors based on observed efficacious vaccination against HER2-positive tumors.
Presenter: Dr Joshua Tobias, Medical University of Vienna.

Highlights and conclusions

• In the preclinical setting (in vivo mouse studies): Targeting HER-2/neu by HER-Vaxx vaccination was associated with concomitant PD-L1 upregulation and the HER2 receptor’s downregulation of expression in the same tumors, resulting in a significantly higher ratio of PD-L1 to HER-2/neu positive metastases.
• In the clinical setting (Phase 1b HERIZON study): Targeting HER2 by HER-Vaxx vaccination was also associated with the upregulation of PD-L1 and downregulation of HER2 expression in the evaluated patient’s primary tumor, conceivably influencing the final disease progression observed in the patient. Tumoral upregulation of PD-L1 and downregulation of HER2 expression have both been linked to resistance and subsequent metastasis development following treatment with the standard of care monoclonal antibody trastuzumab. These observations suggest that targeting HER2 induces upregulation of PD-L1 and a combination therapy targeting both HER2 and the PD1/PD-L1 axis with an immune checkpoint inhibitor may be used clinically and synergistically to treat metastatic HER2+ cancers with prevention of new metastasis development and immune evasion.

Poster Session #4581: Induction of an Inflammatory Tumor Microenvironment with Oncolytic Virus CF33-hNIS-antiPD-L1 Intratumoral Injection in Patients with Metastatic Triple Negative Breast Cancer (mTNBC).
Presenter: Dr Jamie Rand, City of Hope.

Highlights and conclusions

• Intratumoral (IT) treatment with CF33-hNIS-anti-PD-L1 is safe and well-tolerated at dose levels 1 through 3.
• CF33-hNIS-anti-PD-L1 IT injection induces tumor infiltration of CD4+ and CD8+ Tcells which are critical immune cells signalling localised immune activation connected to CF33-hNIS-anti-PD-L1 injection.
• Significant upregulation of PD-L1 within the tumor microenvironment (TME) further suggests immune activation by CF33-hNIS-anti-PD-L1, an important precursor for immune clearance of tumors.
• SPECT imaging after treatment with CF33-hNIS-anti-PD-L1 showed enhancement at injected lesions in 75% of patients, suggesting local viral replication and hNIS expression. This shows successful tracking of viral replication using non-invasive imaging studies.

This clinical trial is ongoing to further assess dose escalation, tumor response, and TME changes at later timepoints and higher dose levels.

The posters are available on Imugene’s website, View Source

On October 24, 2023 Sangamo Therapeutics, Inc. (Nasdaq: SGMO), a genomic medicine company, reported that the European Society of Gene & Cell Therapy (ESGCT) has accepted six Sangamo abstracts for presentation at the 30th Annual Congress being held October 24-27, 2023, in-person in Brussels, Belgium (Press release, Sangamo Therapeutics, OCT 24, 2023, View Source [SID1234636265]). Presentations will focus on the progression of Sangamo’s pre-clinical programs, including data from its neurology epigenetic regulation programs, and advancements in the CAR-Treg pipeline.

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"The data we are presenting at ESGCT reflect the important advances being made across our neurology and CAR-Treg pipelines," said Jason Fontenot, Ph.D., Chief Scientific Officer at Sangamo. "We are excited to showcase these innovations, which reinforce the potential of our science to create transformative treatments for patients suffering with serious diseases."

Data to be presented at the ESGCT Annual Congress include an oral presentation demonstrating how zinc finger activators (ZF-As) may be designed to potentially address neurodevelopmental disorders such as autism spectrum disorder and intellectual disability, for which limited therapeutic treatments currently exist. This presentation will show how ZF-As can be designed to restore normal gene and protein expression of SCN2A in vitro and in vivo. This will be accompanied by a poster presentation demonstrating Shank3 gene activation, mediated by ZF-As as a potential therapeutic approach for Phelan-McDermid syndrome. Both datasets originate from pre-clinical programs previously co-developed in partnership with Novartis.

Additional presentations at the ESGCT Annual Congress will unveil for the first time pre-clinical data showing that autologous MOG-CAR-Tregs may provide a long-lasting treatment option to potentially address the underlying cause of multiple sclerosis, as well as updated pre-clinical data evaluating IL23R-CAR-Tregs as a potentially effective treatment option to address inflammation for patients with Crohn’s disease. Data will also showcase our platform capability of efficient and durable epigenetic cell engineering using compact ZF-Repressors to target immune checkpoints with the potential to improve the anti-tumor activity of T cells in cancer therapy.

ESGCT Annual Congress Presentations and Invited Sessions

Epigenetic Regulation for Neurology:

Zinc Finger Activators restore normal gene and protein expression in a mouse model of SCN2A haploinsufficiency
Abstract No. OR09
Oral Presentation – October 24; 17:00-19:00
Shank3 Gene Activation Mediated by Zinc Finger Activators (ZF-As) as a Therapeutic Approach for Phelan-McDermid Syndrome
Abstract No. P415
Poster Presentation – October 25; 17:00 to 18:15 and October 26; 20:30 to 21:30
Cell Therapy
Regulatory T-Cells (CAR-Tregs)

Myelin Oligodendrocyte Glycoprotein (MOG)-CAR-Tregs – A novel approach to treat multiple sclerosis
Abstract No. P475
Poster Presentation – October 25; 17:00 to 18:15 and October 26; 20:30 to 21:30
Evaluation of IL23R as a target for CAR-Tregs at the site of inflammation in subjects with Crohn’s Disease
Abstract No. P487
Poster Presentation – October 25; 17:00 to 18:15 and October 26; 20:30 to 21:30
Multimerization of Chimeric Antigen Receptor (CAR) binding domains: A solution to assess tissue specificity of low to medium affinity scFv
Abstract No. P503
Poster Presentation – October 25; 17:00 to 18:15 and October 26; 20:30 to 21:30
CAR-T in Oncology

Multiplex targeting of immune checkpoints with compact zinc finger repressors to improve anti-tumor activity of T cells
Abstract No. P212
Poster Presentation – October 25; 18:15 to 19:30 and October 26; 19:30 to 20:30
All ESGCT presentations are available on the Sangamo website.

On October 24, 2023 Novartis reported its Third Quarter and Nine Months 2023 report (Presentation, Novartis, OCT 24, 2023, View Source [SID1234636264]).

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On October 23, 2023 ImmunityBio, Inc. (NASDAQ: IBRX), a clinical-stage immunotherapy company, reported it has completed the resubmission of its Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for N-803 (Anktiva), a first-in-class IL-15 superagonist, plus Bacillus Calmette-Guérin (BCG) for the treatment of BCG-unresponsive non-muscle-invasive bladder cancer carcinoma in situ (CIS) with or without Ta or T1 disease (Press release, ImmunityBio, OCT 23, 2023, View Source [SID1234638824]).

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The BLA is supported by the results of ImmunityBio’s studies in bladder cancer including the pivotal QUILT-3.032 study (NCT03022825), published in NEJM Evidence1 in November 2022. An update of the duration of response regarding the responders identified by the FDA in the efficacy population for BCG unresponsive subjects with high-risk CIS disease was provided in the BLA resubmission. This update demonstrated a prolonged duration of remission in responding subjects, with a median duration of CR not yet reached with a follow-up in responders exceeding 28 months, and a safety profile as reported previously. The updated duration of CR in these responding BCG-unresponsive subjects showed that the probability of maintaining a CR for ≥ 24 months was 60%, with a cystectomy free rate at ≥ 24 months of over 90%.

In addition, ImmunityBio provided an update on the long-term follow-up (QUILT-205) of subjects receiving N-803 plus BCG for CIS ± Ta/T1 in the Phase 1b (QUILT-2.005) trial, examining the survival of the nine subjects entering the trial since 2014. All 9 subjects (100%) achieved a complete remission and the results are published in Oncoimmunology2-5. Of the nine subjects, two were deceased from causes other than bladder cancer and one was lost to follow-up. Of the 6 subjects available for follow-up (QUILT-205), 6 out of 6 subjects (100%) demonstrated long-term complete remission with bladder preservation over a median survival period of 8.8 years and all 6 subjects have avoided a cystectomy to date.

ImmunityBio’s IL-15 superagonist N-803 (Anktiva)
The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of the natural killer (NK) and T cells. N-803 is a novel investigational IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. Its proposed mechanism of action is direct specific stimulation of CD8+ T cells and NK cells through beta gamma T-cell receptor binding with generation of memory T-cells while avoiding T-reg stimulation. N-803 is designed to have improved pharmacokinetic properties, longer persistence in lymphoid tissues and enhanced anti-tumor activity compared to native, non-complexed IL-15 in vivo.

N-803 is currently being evaluated in adult patients in two clinical NMIBC trials. QUILT-2.005 is investigating use of N-803 in combination with BCG for patients with BCG-naïve NMIBC; QUILT-3.032 is studying N-803 in combination with BCG in patients with BCG-unresponsive NMIBC CIS and Papillary Disease.

N-803 is investigational. Safety and efficacy have not been established by any Health Authority or Agency, including the FDA.

Selected Publications:

Chamie, K., Chang, S. S., Kramolowsky, E., Gonzalgo, M. L., Agarwal, P. K., Bassett, J. C., Bjurlin, M., Cher, M. L., Clark, W., Cowan, B. E., David, R., Goldfischer, E., Guru, K., Jalkut, M. W., Kaffenberger, S. D., Kaminetsky, J., Katz, A. E., Koo, A. S., Sexton, W. J., … Soon-Shiong, P. (2023). IL-15 Superagonist NAI in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer. In NEJM Evidence (Vol. 2, Issue 1). Massachusetts Medical Society. View Source
Rosser CJ, Tikhonenkov S, Nix JW, Chan OTM, Ianculescu I, Reddy S, Soon-Shiong P. Safety, Tolerability, and Long-Term Clinical Outcomes of an IL-15 analogue (N-803) Admixed with Bacillus Calmette-Guérin (BCG) for the Treatment of Bladder Cancer. Oncoimmunology. 2021 May 3;10(1):1912885. doi: 10.1080/2162402X.2021.1912885. PMID: 33996264; PMCID: PMC8096327.
Chamie K, Chang SS, Gonzalgo M, Kramolowsky EV, Sexton WJ, Bhar P, et al.. Final clinical Results of Pivotal Trial of IL-15rαfc Superagonist N-803 with BCG in BCG-Unresponsive CIS and Papillary Non-Muscle Invasive Bladder Cancer (NMIBC). J Clin Oncol (2022) 40(16_suppl):4508. doi: 10.1200/JCO.2022.40.16_suppl.4508
Chamie K, Chang SS, Gonzalgo M, Kramolowsky EV, Sexton WJ, Bhar P, et al.. Phase II/III Clinical Results of IL-15rαfc Superagonist N-803 with BCG in BCG-Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) Carcinoma in Situ (CIS) Patients. J Clin Oncol (2021) 39(suppl 6):510. doi: 10.1200/JCO.2021.39.6_suppl.510
Huang J, Shiao SL, Furuya H, Rosser CJ. Immunogenomic Analysis of Exceptional Responder to ALT-803 (IL-15 Analogue) in BCG Unresponsive Nonmuscle Invasive Bladder Cancer: A Case Series and Review of the Literature. J Immunother. 2019 Nov/Dec;42(9):354-358. doi: 10.1097/CJI.0000000000000269. PMID: 31107371; PMCID: PMC6783344.

On October 23, 2023 Chimeric Therapeutics (ASX:CHM, "Chimeric" or the "Company"), an Australian leader in cell therapy, reported positive clinical data for CLTX CAR T in heavily pretreated, late stage, recurrent Glioblastoma patients in the Phase 1A trial, conducted at City of Hope, one of the largest cancer research and treatment organizations in the United States (Press release, Chimeric Therapeutics, OCT 23, 2023, View Source [SID1234636406]). The information provided herein is based on preliminary study data. The trial remains ongoing and will continue to be monitored and evaluated.

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Patients treated in the Phase 1A trial were heavily pretreated, on average receiving CLTX CAR T as 4th line therapy (range 3-5th line). Historical trials in recurrent GBM have generally been limited to patients treated in 2nd line.

Patients treated across all 4 dose levels of the trial achieved a 55% Disease Control Rate, exceeding expectations and historical disease control rates of 20-37% for patients treated in 2nd line.

~9.9, 95% CI [5.8, NA] months median survival was demonstrated for patients that achieved disease control, with one patient exceeding 18 months survival, two patients exceeding 14 months survival and with 3 patients remaining alive and in follow up. Survival expectations for patients after first line therapy are generally ~7 months.

The interim results suggest that CLTX CAR T was generally well tolerated, with no dose limiting toxicities (DLT’s), no Cytokine Release Syndrome (CRS) and no Tumor Lysis Syndrome (TLS). Grade 3 events were generally manageable and most often attributed to disease progression.

"The CLTX CAR T dose escalation preliminary data are truly encouraging and have exceeded our expectations, particularly given that the patients enrolled were heavily pretreated and very late stage," said Jennifer Chow, CEO and Managing Director of Chimeric Therapeutics.

"Historical therapies for recurrent Glioblastoma have generally been studied in patients with a median of 1 prior line of therapy. In contrast, the CLTX CAR T study enrolled patients with a median of 3 prior lines of therapy. The disease control rate of 55% is beyond that observed in patients treated with 2nd line therapy in historical clinical trials. Most exciting to us though, is that despite the advanced nature of the patients studied, CLTX CAR T demonstrated median survival of ~10 months for those that achieved disease control, with two patients demonstrating survival beyond 14 months. These data strongly demonstrate the potential utility of CLTX CAR T for patients with recurrent GBM."

Chimeric has now advanced development of CLTX CAR T to a Phase 1B clinical trial currently open for enrollment at the Sarah Cannon Transplant & Cellular Therapy Program at St. David’s South Austin Medical Center in Austin, Texas. The trial is being conducted under a US IND and is a two-part clinical trial (NCT04214392).

Part A of the trial will enroll 3-6 clinical trial participants at 440 X 106 CHM 1101 cells, the highest dose tested in the Phase 1A clinical trial at City of Hope. Based on the safety and efficacy demonstrated in the interim results of the Phase 1A City of Hope clinical trial, Chimeric will advance development of CLTX CAR T to Part B of the trial, an expansion cohort designed to confirm the recommended Phase 2 dose and administration schedule. Part B of the trial will enroll 12-26 additional patients.

"The preliminary data from the Phase 1A trial of CLTX CAR T reinforce our confidence in CLTX CAR T cell therapy," said Dr Jason Litten, Chief Medical Officer of Chimeric Therapeutics. "The safety profile and potential survival benefit demonstrated in these difficult-to-treat patients inspire us to advance clinical development of CLTX CAR T cell therapy. We are actively enrolling patients in our Phase 1B dose confirmation trial and now look forward to advancing our study to a dose expansion cohort in 2024".

Upon successful completion of the dose expansion cohort, Chimeric intends to design and initiate a registrational trial, in alignment with regulatory guidance and feedback. The City of Hope Phase 1A study enrolled clinical trial participants with MMP2+ recurrent or progressive GBM across four dose levels. Behnam Badie, M.D., City of Hope Chief of Division of Neurosurgery, is the trial’s principal investigator. The trial is being conducted at City of Hope’s Los Angeles campus.

Chimeric Therapeutics has licensed the exclusive global rights to intellectual property covering the chlorotoxin CAR-T cells from City of Hope, one of the largest cancer research and treatment organizations in the United States.

INVESTOR WEBINAR – 11am AEDT TODAY

Chimeric is pleased to host a webinar regarding today’s announcement, with all shareholders and interested parties welcome to attend. Chimeric’s CEO and Managing Director Jennifer Chow and Chimeric’s Chief Medical Officer, Dr Jason Litten will host the session and provide further discussion and context around the CLTX CAR T data.

An opportunity to ask questions will also be provided. When: 11am AEDT, Monday 23 October 2023

Register at: View Source Upon registering attendees will receive an email containing information about joining the webinar.

A recording will be available at the above link soon after the conclusion of the live session, with the replay to also be made available via Chimeric’s website and social media channels.

Questions can be sent in advance of the webinar to [email protected]