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]

On October 23, 2023 OSE Immunotherapeutics SA (ISIN: FR0012127173; Mnemo: OSE) reported that first Phase 1 results for BI 770371, a novel anti-SIRPα monoclonal antibody evaluated in advanced solid tumors, have been presented, at the European Society for Medical Oncology conference, held in Madrid, Spain (October 20 – 24, 2023) (Press release, OSE Immunotherapeutics, OCT 23, 2023, View Source [SID1234636289]).

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BI 770371 is an IgG1 mAb that recognizes both the V1 and V2 variants of SIRPα. In many cancer types, CD47 forms a potent ‘don’t eat me’ signaling complex with SIRPα that triggers a cascade of events that enables cancer cells to avoid detection by the innate immune system and inhibits the ability of macrophage cells to fight cancer. By blocking the interaction between SIRPα and cluster of differentiation 47 (CD47), SIRPα antagonism enhances innate immunity and restores the immune function of myeloid cells in the tumor microenvironment.

Nicolas Poirier, Chief Executive Officer of OSE Immunotherapeutics, commented:

"We congratulate our partner Boehringer Ingelheim for this important new achievement, performed in the frame of our global collaboration and license agreement, which demonstrates their commitment to selective SIRPα inhibitors targeting myeloid cells. We are very pleased to potentially make our selective SIRPα inhibitor technology available to more patients through this strategic collaboration. With the V1 and V2 alleles being similarly expressed across humans in western countries, and V2 being more prevalent in the Asian region, the additional BI 770371 program highlights a new step forward in our partnership with Boehringer Ingelheim aiming to provide this selective SIRPα innovation for the benefits of more patients."

The BI 770371 development program will extend the therapeutic potential of selective SIRPα antagonists in various diseases or disorders, covering the most prevalent allelic variants* of SIRPα, V1 SIRPα and V2 SIRPα expressed on myeloid cells.

Boehringer Ingelheim is currently evaluating BI 770371 as monotherapy and in combination with ezabenlimab, a PD1 inhibitor (BI 754091), in an open-label, dose escalation/dose expansion Phase I clinical trial (NCT05327946) conducted in Canada, USA and Japan in patients with advanced solid tumours. The first clinical results of BI 770371 presented at ESMO (Free ESMO Whitepaper) 2023 conference (Madrid, Abstract #697P) showed that adverse events were manageable during the on-treatment period, Maximal Tolerated Dose (MTD) has not been reached. This clinical trial is ongoing. Boehringer Ingelheim is also evaluating BI 765063 (formerly OSE-172) in different combinations with patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or hepatocellular carcinoma (HCC) in a Phase 1b trial conducted in the United States, Europe and Asia (NCT05249426).

ESMO, Abstract #697P title:
Open-label, Phase I dose escalation/expansion trial of the anti-SIRPa monoclonal antibody BI 770371 in patients with advanced solid tumours, alone or in combination with the anti-PD-1 monoclonal antibody ezabenlimab -NCT05327946

Martin E. Gutierrez1*, Rahima Jamal2, Noboru Yamamoto3, Toshihiko Doi4, Gunther Kretschmar5, Javier Ferrada5, Stephan Wojciekowski6, Manish R. Patel7
1 Hackensack University Medical Center at Hackensack Meridian Health, Hackensack, NJ, USA; 2 Centre Hospitalier de l’Université de Montréal (CHUM), Centre de recherche du CHUM, Montreal, QC, Canada; 3 National Cancer Center Hospital, Tokyo, Japan; 4 National Cancer Center Hospital East, Kashiwa, Japan; 5 Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA; 6 Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany; 7 Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA

On October 23, 2023 Iksuda Therapeutics (Iksuda), the developer of class leading antibody drug conjugates (ADCs) with enhanced tumour specificity, reported that the first patient has completed a first cycle of therapy with IKS014, a human epidermal growth factor receptor 2 (HER2) ADC targeting patients with advanced HER2+ solid tumours. This follows positive data from Phase 1 clinical trials through Fosun Pharma, which is now progressing FS-1502 (IKS014) through Phase 2 and Phase 3 trials in China (Press release, Iksuda Therapeutics, OCT 23, 2023, View Source [SID1234636288]).

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The open-label, interventional study (View Source) is designed to evaluate the safety and tolerability of increasing dose levels of IKS014 to establish a recommended Phase 2 dose. The second, dose-expansion, phase of the study (Phase 1b) is to further evaluate the safety, pharmacokinetics / pharmacodynamics, and efficacy of IKS014 at the recommended Phase 2 dose. The study is currently enrolling patients at five planned locations in Australia. The Phase 1b trial is expected to read out in 2H 2025.

Dr Dave Simpson, Chief Executive Officer, Iksuda Therapeutics, said:

"The dosing of the first patient in our Phase 1 trial of IKS014 marks a significant milestone for Iksuda: our transition to being a clinical-stage company. We hope that this trial of IKS014 could lead to improved treatment options for patients with HER2+ solid tumours."

About IKS014

IKS014 is a potential best-in-class antibody drug conjugate, benefiting from tumour selective activation and release of the cytotoxic agent monomethyl auristatin F (MMAF). In preclinical trials, it displayed impressive activity in high- and low-HER2 expressing tumours with significantly higher non-severely toxic dose (HNSTD) vs other HER2-directed drugs. Iksuda gained exclusive world-wide rights (excluding Greater China and South Korea) to IKS014 from LegoChem Biosciences. (View Source) Fosun Pharma holds the licence to the ADC in Greater China where it is designated FS-1502. Fosun is currently conducting a Phase 2 clinical trial in China in patients with a range of solid tumours and has also initiated a Phase 3 trial in patients with advanced breast cancer.

On October 23, 2023 HighField Biopharmaceuticals, a clinical stage immuno-oncology company using lipid-based therapeutics to treat cancer, reported results of its Phase 1a study of HF1K16 showing three of five patients with recurrent and refractory glioma had maintained disease control for more than 8 months with one patient experiencing complete response (Press release, HighField Biopharmaceuticals, OCT 23, 2023, View Source [SID1234636287]). HF1K16 is a drug encapsulated immune modulating liposome containing all-trans retinoic acid.

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"These encouraging results show HF1K16 is well tolerated and patients have experienced significant disease control," said Yuhong Xu, CEO of HighField. "We are currently enrolling additional glioma patients in our Phase 1b/2 extension trial to confirm these outcomes and expect to have the results in the first quarter of 2024."

Dr. Xu and HighField Chief Business Officer Donald Wyatt will attend BIO-Europe November 6 – 8, 2023, in Munich, Germany, to discuss the company’s unique lipid-based drug, including details of the Phase 1a trial. Dr. Xu and Mr. Wyatt can be contacted through the conference’s online Partnering platform.

Of the three patients who had experienced disease control, one patient achieved complete remission after 12 months of treatment and has been cancer free afterwards for 7 months. One of the other two patients, with grade IV glioblastoma, maintained stable disease for more than 4 months. The third patient had stable disease for nearly 3 months and survival to date for more than 9 months. HF1K16 was well tolerated with no high grade adverse effects at all dose levels.

HF1K16 is a unique liposome construct of ATRA, a small molecule metabolite of vitamin A. It is administered by infusion, travels through the blood stream and infiltrates the tumor microenvironment. ATRA is released and initiates the maturation of myeloid-derived suppressor cells (MDSCs).

MDSCs are immature myeloid cells which have not differentiated. ATRA promotes the maturation and differentiation of MDSCs into functional cells, such as dendritic cells, which then summon T cells to attack the cancer.

The Phase 1b/2 trial, underway in China, and will assess safety and efficacy as well as evaluate changes in MDSC numbers and phenotypes. See NCT05388487 at clinicaltrials.gov.