On December 12, 2023 ISA reported positive anti-tumor response data with ISA101b, an HPV16 directed therapeutic cancer vaccine given in combination with Libtayo, an anti-PD1 checkpoint inhibitor (CPI) (Press release, ISA Pharmaceuticals, DEC 12, 2023, View Source [SID1234638495]). The data were generated in the OpcemISA trial, a large scale randomized double blind study that is ongoing in patients with advanced oropharyngeal cancer (OPC), a type of head and neck cancer. It is the first time that the combination of a tumor-specific therapeutic vaccine and a CPI has generated such high response rates, albeit in a predefined subpopulation of metastatic cancer patients.

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ISA101b is a therapeutic cancer vaccine targeting cancers caused by the human papillomavirus type 16 (HPV16). More than 60 percent of head-and-neck cancers are HPV16-related, and incidence rates are going up. ISA101b elicits a powerful and targeted T-cell immune response to the HPV16 virus.

OPC is a solid cancer with a high unmet medical need that does not always respond to immunotherapy. Best responses in the OpcemISA trial are found in a subcategory of patients with characteristics suitable for immunostimulatory treatments.

Study design & results

A total of 199 first- and second-line patients with recurrent/metastatic HPV16+ OPC were enrolled in the OpcemISA trial. Patients were randomized to receive either ISA101b plus CPI, or placebo plus CPI. The primary endpoint was the objective response rate (ORR) at 6 months, confirmed by independent central review. The secondary endpoints included drug safety, progression free survival (PFS) and overall survival (OS). Further details can be found at clinicaltrials.gov (NCT03669718).

Whereas the addition of ISA101b to the CPI led to a doubling of the ORR (from 26.7% to 51.9%) in a large subgroup of patients, the study as a whole did not meet this primary endpoint. Patients in the aforementioned subgroup, predefined based on a validated biomarker, also showed a clear overall survival benefit compared to the placebo arm. ISA101b was well tolerated.

Gerben Moolhuizen, Chief Executive Officer of ISA, said, "Recurrent and/or metastatic head and neck cancer is notoriously difficult to treat. Patients suffering from this terrible disease need new treatment options. In our OpcemISA study, ISA101b shows compelling results in a large, predefined subset of patients. This provides us with a clear development path to make ISA101b a treatment option for these patients."

Phase 3 and beyond

ISA is preparing for a confirmatory Phase 3 trial in this subpopulation of patients. This subgroup represents an important proportion of head and neck cancer patients, and an attractive commercial opportunity. The OpcemISA trial was part of a clinical collaboration between ISA and Regeneron. Regeneron has elected not to exercise its option on the ISA101b asset. ISA is currently in discussions with potential partners with interest in ISA101b and ISA’s technology platform in general.

On December 12, 2023 Immodulon, a late-stage clinical biotechnology company focused on developing a broad spectrum immunomodulator to improve the lives of patients suffering from difficult-to-treat cancers, reported the formation of a new Scientific Advisory Board comprising leading global experts in the field of clinical oncology (Press release, Immodulon Therapeutics, DEC 12, 2023, View Source [SID1234638494]). The new SAB will be chaired by Prof. Dr. med. Thomas Seufferlein, Director, Department of Gastroenterology, University of Ulm, Germany, and will complement the experience of Immodulon’s new management team to support the advancement of IMM-101 into a pivotal trial for pancreatic cancer as well as broader pipeline progress.

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"I am excited about the opportunity to partner with such an esteemed group of scientific advisors who are committed to supporting the development of IMM-101 to treat immunologically cold tumors, including pancreatic cancer," said Josefine Roemmler-Zehrer, MD, Associate Professor, and Immodulon’s Chief Medical Officer. "I am confident that their guidance will be crucial to moving IMM-101 into a pivotal trial for pancreatic cancer, following the completion of a positive Phase 2 trial, and accelerating our efforts to bring its therapeutic potential closer to cancer patients in need."

"I am delighted to chair this board of global experts in pancreatic cancer. My fellow SAB members and I are looking forward to supporting the Immodulon team in their efforts to develop IMM-101 into an effective treatment for patients with metastatic pancreatic cancer," said Prof. Dr. Thomas Seufferlein, Chair of Immodulon’s Scientific Advisory Board.

The new SAB consists of the following members:

Prof. Dr. med. Thomas Seufferlein (Chairman), University of Ulm, Ulm, Germany
Dr. Jean-Pierre Bizzari, MD, Former EVP, Group Head ClinicalDevelopment Oncology at Celgene
Prof. David Chang, MBBS, MS, FRACS, FRCS, PhD, University of Glasgow, Glasgow, UK
Prof. Angus Dalgleish, MD, FRCP, FRACP, FRCPath, St. Georges University Hospital, London, UK
Dr. Andrew Gaya, BSc, MB SC, MRCP, FRCR, MD, Guy’s and St Thomas’ Hospital, London, UK
Prof. Jeeyun Lee, MD, Sungkyunkwan University, Samsung MC,Seoul, ROK
Prof. Andrew MacDonald, BSc, PhD, University of Manchester, Manchester, UK
Dr. Victoria Manax, MD, Managing Partner MRCD Consulting
Prof. Josep Tabernero, MD, PhD, Vall d’Hebron University, Barcelona, Spain
Prof. Dr. Margaret Tempero, MD, USCF, CA, United States
Prof. Dr. Eric Van Cutsem, MD, University of Leuven, Belgium

On December 12, 2023 Ichnos Sciences, a global clinical-stage biotechnology company developing innovative multispecific immune cell engager antibodies in oncology, reported data during three poster presentations at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) 2023 Annual Meeting and Exposition in San Diego, California (Press release, Ichnos Sciences, DEC 12, 2023, View Source [SID1234638492]).

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The studies showcased encouraging safety profiles, dose-dependent pharmacokinetics, and efficacy signals, marking significant progress in the fight against relapsed or refractory multiple myeloma.

"The results of these studies are a validating mile marker for our proprietary BEAT1 multispecific platform’s innovative mechanism of action," said Eugene Zhukovsky, Ichnos’ Chief Scientific Officer. "Our platform shows promise to unleash a powerful combination that can specifically target multiple surface proteins of tumor cells. This novel approach means stronger and more specific binding of immune cells to tumor cells, offering a beacon of hope for patients in dire need of treatment options as they face challenging hematologic malignancies."

1. Dose Escalation of ISB 1342, a Novel CD38xCD3 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM):

Safety and tolerance: Demonstrated treatment with ISB 1342 was manageable at higher dose levels evaluated, with mild to moderate CRS, no ICANS, and no increased risk of infection observed.
Dose-dependent pharmacokinetics and biomarkers: Following IV infusion, ISB 1342 showed dose-linear increase in serum exposures across the evaluated dose range. Increases in several T-cell activation-related biomarkers (CD69 by flow, and serum cytokines withing 24hrs, such as IFNg, TNFa, IL-2, IL-6 and IL-10), were consistently observed following ISB 1342 dosing supporting proof of mechanism.
Efficacy signals: Positive results in patient groups at higher dose levels (8 and 16 μg/kg cohorts) align with predicted effectiveness based on a sophisticated preclinical quantitative system pharmacology (QSP) model, supporting the drug’s potential success in treating multiple myeloma.
2. Initial Dose Escalation of ISB 1442, a Novel CD38 Biparatopic x CD47 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM):

Safety and tolerance: Demonstrated treatment with ISB 1442 was well tolerated at the dose levels evaluated, with observed clinical cytokine release syndrome (CRS) events being low grade and potentially related to macrophage activation following ISB 1442 administration.
Dose-dependent pharmacokinetics: Showed dose-linear increase in serum concentration up to DL 3 (60 mg), followed by a super-proportional increase in serum exposure most evident between DL3 (60 mg) and DL4 (150 mg).
Mechanism of action: Increase in macrophage-associated markers are consistent with a potential mechanism of action involving macrophage activation enhanced by the effector function modifications incorporated into the design of ISB 1442.
3. A Phase 1, First-in-Human, Dose Escalation and Dose-Expansion Study of a BCMAxCD38xCD3 Targeting Trispecific Antibody ISB 2001 in Subjects with Relapsed / Refractory Multiple Myeloma (RRMM):

ISB 2001 debut: A BCMAxCD38xCD3 trispecific antibody1 based on Ichnos’ proprietary TREAT2 platform, which promotes strong avidity induction and enables efficient and potent killing of multiple myeloma (MM) cells. Dual TAA targeting with ISB 2001 may overcome escape mechanisms associated with BCMA and CD38 targeted therapies, including approved T cell engagers, ADC or cell therapies.
Study design: Phase 1 study (NCT05862012) employing a subcutaneous dosing strategy with a step-up dosing approach, aiming to confirm efficacy and tolerability in patients with RRMM. The first-in-human dose was derived using advanced preclinical modeling, emphasizing safety with a preemptive step-up dosing strategy.
Future direction: The study is currently open for enrollment. Part 2 aims to confirm safety, select the recommended Phase 2 dose (RP2D), and explore secondary and exploratory endpoints.
All three of Ichnos’ presentations and corresponding data are available for review on the Ichnos website. More information about the three oncology assets highlighted at the meeting, and the rest of Ichnos’ pipeline can be found at this link.

On December 12, 2023 Galapagos NV (Euronext & NASDAQ: GLPG) reported additional encouraging clinical data from the ongoing Phase 1/2 CD19 CAR-T studies, EUPLAGIA-1 with GLPG5201 and ATALANTA-1 with GLPG5101, in patients with relapsed/refractory chronic lymphocytic leukemia (rrCLL), with or without Richter transformation, and non-Hodgkin lymphoma (rrNHL), during two poster sessions at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting taking place in San Diego, from 9-12 December (Press release, Galapagos, DEC 12, 2023, View Source [SID1234638491]).

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"We are very pleased to share promising new data from our ongoing CD19 CAR-T cell therapy programs, which further highlight that treatment with both GLPG5201 and GLPG5101 has the potential to deliver clinically meaningful results in these severely compromised patient populations. We are particularly encouraged that the results suggest that a vein-to-vein time of only seven days with fresh CAR-T cells is feasible, which would address the urgent needs of cancer patients who cannot afford to wait for treatment," said Dr. Jeevan Shetty, Head of Clinical Development Oncology at Galapagos. "These results demonstrate the potential of our innovative development and manufacturing approach in CAR-T cell therapy to transform the lives of patients. This data bolsters our confidence in the GLPG5201 and GLPG5101 programs for the treatment of patients with rrCLL and rrNHL, and the potential of our CAR-T pipeline beyond these initial indications."

Galapagos has an interactive booth (#3419) at the ASH (Free ASH Whitepaper) congress and will organize a Company Showcase in room 5 A (at the congress center, upper level) on 9 December at 11:30 am PT/22:30 CET, focusing on Galapagos’ 7-day vein-to-vein, fresh-to-fresh CAR-T manufacturing model at the point-of-care. In addition, Galapagos will host a media round table on 10 December at 7:30 am PT/16:30 CET at the Hilton Gaslamp Quarter San Diego, with experts discussing innovative approaches in CAR-T treatment that have the potential to transform the lives of patients around the world, and a KOL event for analysts and investors on 10 December at 11:00 am PT/20:00 CET at the Marriott Gaslamp Quarter San Diego.

GLPG5201 in rrCLL with or without Richter transformation (RT)
Patient recruitment of the Phase 1 dose-finding part of EUPLAGIA-1 has been completed and as of 6 September 2023 (cut-off date), 15 patients (6 at dose level 1 (DL1); and 9 at dose level 2 (DL2)) were enrolled, all of whom were diagnosed with rrCLL, with 9 of 15 with RT. Efficacy data as of Day 28 are available for 14 patients; 1 patient did not yet reach the Day 28 follow-up visit at the time of the analysis. The results (cut-off date: 6 September 2023) included in the poster are summarized below:

GLPG5201 showed an encouraging safety profile with most treatment emergent adverse events (TEAEs) of Grade 1 or 2, mostly hematological. Cytokine release syndrome (CRS) Grade 1 or 2 was observed in 47% of the patients, and no CRS Grade ≥ 3 or any immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. No deaths were reported.
Overall, 13 of 14 efficacy evaluable patients responded to treatment (Objective Response Rate (ORR) of 93%) and 8 of 14 patients achieved a Complete Response Rate (CRR of 57%). 8 of 9 patients with RT responded to treatment (ORR of 89%) and 6 of 9 RT patients achieved a Complete Response (CRR of 67 %). At time of analysis, 10 of 13 of responding patients (77%) were in ongoing response with a median follow-up of 6 months; 2 of 3 patients who progressed after an initial response had confirmed CD19-negative disease.
On the higher dose level (DL2), 8 of 8 patients responded to treatment (ORR of 100%), 5 of 8 patients achieved a Complete Response (CRR of 63%), and 6 of 6 patients with RT responded to treatment (ORR of 100%).
DL2 was selected as the recommended dose for the Phase 2 part of the study.
The data suggest that Galapagos’ CAR-T point-of-care manufacturing platform can deliver fresh product in a median vein-to-vein time of seven days.
Strong and consistent in vivo CAR-T expansion levels and a product consisting of early phenotype T cells were observed in all doses tested.
GLPG5101 in rrNHL
To further build a robust data package, patient recruitment of the Phase 1 dose-finding part of ATALANTA-1 is ongoing. As of 1 September 2023 (cut-off date), 14 heavily pre-treated rrNHL patients with diffuse large B cell lymphoma, mantle cell lymphoma and indolent lymphoma were enrolled (7 at DL1 and 7 at DL2). In parallel, enrollment of the Phase 2 expansion study is ongoing, and the first 9 patients have been dosed. The results (cut-off date: 1 September 2023) included in the poster are summarized below:

Phase 1 part of the study:
GLPG5101 showed an encouraging safety profile. Most TEAEs were Grade 1 or 2 and the majority of the few Grade ≥ 3 events hematological. No CRS Grade > 3 and no ICANS Grade ≥ 2 were observed.
12 of 14 evaluable patients responded to treatment (ORR of 86%), with 11 of 14 patients achieving a Complete Response (CRR of 79%). 6 of 7 patients treated with the higher dose level (DL2) responded to treatment (ORR of 86%) and achieved a Complete Response (CRR of 86%). At the time of the analysis, 8 of 12 responding patients (67%) had an ongoing response, with a duration up to 15 months (median follow-up of 8.6 months); 2 of the 4 patients who progressed after an initial response had a CD19 positive relapse and 1 had confirmed CD19-negative disease.
Phase 2 part of the study:
GLPG5101 showed an encouraging safety profile with most TEAEs of Grade 1 or 2; the majority of Grade ≥ 3 events were hematological. No CRS Grade > 2 and ICANS was seen in one patient (Grade 3).
6 of 7 evaluable patients responded to treatment (ORR of 86%) and a Complete Response was observed in 4 of 7 patients (57%). At the time of the analysis, all 6 responding patients (100%) had an ongoing response with a median follow-up of 3.2 months.
The data suggest that Galapagos’ point-of-care platform can deliver fresh product in a median vein-to-vein time of seven days.
Strong and consistent in vivo CAR-T expansion levels and a product consisting of early phenotype T cells were observed in all doses tested.
Natalia Tovar, MD, PhD, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona (Spain) presented the analysis on the Phase 1 part EUPLAGIA-1 in patients with rrCLL, with or without RT. Marie José Kersten, MD, PhD, Professor of Hematology and Head of the Department of Hematology at the Academic Center in Amsterdam (The Netherlands) presented the analysis on the Phase 1 and Phase 2 parts of ATALANTA-1 in patients with rrNHL.

The poster presentations are available in the poster hall and the ASH (Free ASH Whitepaper) website:

Abstract Title Authors Presentation details
Seven-day Vein-to-Vein Point-of-Care Manufactured CD19 CAR T Cells (GLPG5201) in Relapsed/Refractory CLL/SLL including Richter’s Transformation: Results from the Phase 1 Euplagia-1 Trial Natalia Tovar, Valentin Ortiz-Maldonado, Nuria Martinez-Cibrian, Sergi Betriu, Daniel Esteban, Ana Triguero, Nadia Verbruggen, Anna D.D. van Muyden, Maike Spoon, Margot J. Pont Abstract
Poster Number: 2112
Date: 9 Dec, 5:30–7:30 pm PT
Session: Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster I
Seven-day Vein-to-Vein Point-of-Care Manufactured CD19 CAR T Cells (GLPG5101) in Relapsed/Refractory NHL: Results from the Phase 1 Atalanta-1 Trial Marie José Kersten, Kirsten Saevels, Sophie Servais, Yves Beguin, Joost Vermaat, Nadia Verbruggen, Anna DD Van Muyden, Margot J Pont, Maria T Kuipers, Sébastien Anguille Abstract
Poster Number: 2113
Date: 9 Dec, 2023, 5:30–7:30 pm PT
Session: Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster I
About Galapagos’ innovative approach to CAR-T manufacturing near the point-of-care
Galapagos’ decentralized, innovative point-of-care CAR-T manufacturing platform consists of a proprietary end-to-end xCellit workflow management and monitoring software system, a decentralized, functionally closed, automated manufacturing platform for cell therapies (using Lonza’s Cocoon) and a proprietary quality control (QC) testing and release strategy. The combination of these three core components allows for the administration of a fresh product, a median vein-to-vein time of seven days (i.e. the time between T-cell collection and CAR-T infusion), and greater physicians oversight throughout the process.

About the EUPLAGIA-1 study (EudraCT 2021-003815-25)
EUPLAGIA-1 is an ongoing Phase 1/2 open-label, multi-center study evaluating the feasibility, safety, and efficacy of point-of-care manufactured GLPG5201 in patients with relapsed/refractory lymphocytic leukemia (rrCLL) and small cell lymphocytic lymphoma (rrSLL), with or without Richter transformation (RT). GLPG5201 is a second generation anti-CD19/4-1BB CAR-T product candidate, administered as intravenous infusion of a fresh product candidate in a single fixed dose. Patients with CD19+ rrCLL or rrSLL with ≥2 lines of prior therapy are eligible to participate, and patients with RT are eligible regardless of prior therapy. The primary objective of the Phase 1 part of the study was to evaluate safety and determine the recommended dose for the Phase 2 part of the study. The dose levels that were evaluated in the Phase 1 part of the study are 35×106 (DL1), and 100×106 (DL2) CAR+ viable T cells.

About chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin. CLL affects B-cells in the blood and bone marrow.1 RT is an uncommon clinicopathological condition observed in patients with CLL. It is characterized by the sudden transformation of the CLL into a significantly more aggressive form of large cell lymphoma and occurs in approximately 2-10% of all CLL patients. CLL usually follows an indolent course and is an incurable disease. Patients who develop relapsed and refractory disease and become resistant to new agents have a dismal prognosis and a high unmet medical need for new therapeutic options such as CAR-T cells. With estimated incidence of 4.7 new cases per 100,000 individuals, CLL is the most prevalent lymphoid malignancy and is the most common adult leukemias in the US and in Europe.2

About the ATALANTA-1 study (EudraCT 2021-003272-13)
ATALANTA-1 is an ongoing Phase 1/2, open-label, multicenter study to evaluate the feasibility, safety, and efficacy of point-of-care manufactured GLPG5101, a CD19 CAR-T product candidate, in patients with relapsed/refractory non-Hodgkin’s lymphoma (rrNHL). GLPG5101 is a second generation anti-CD19/4-1BB CAR-T product candidate, administered as an intravenous infusion of a fresh product candidate in a single fixed dose. Each enrolled patient will be followed for 24 months. The primary objective of the Phase 1 part of the study was to evaluate safety and to determine the recommended dose for the Phase 2 part of the study. Secondary objectives include assessment of efficacy and feasibility of point-of-care manufacturing of GLPG5101. The dose levels that were evaluated in Phase 1 are 50×106 (DL1) and 110×106 (DL2) and 250×106 (DL3) CAR+ viable T cells.

The primary objective of the Phase 2 part of the study is to evaluate the Objective Response Rate (ORR) while the secondary objectives include Complete Response rate (CRR), duration of response, progression free survival, overall survival, safety, pharmacokinetic profile, and feasibility of point-of-care manufacturing.

About non-Hodgkin’s lymphoma
Non-Hodgkin’s lymphoma is a cancer originating from lymphocytes, a type of white blood cell which is part of the body’s immune system. Non-Hodgkin’s lymphoma can occur at any age although it is more common in adults over 50 years old. Initial symptoms usually are enlarged lymph nodes, fever, and weight loss. There are many different types of non-Hodgkin’s lymphoma. These types can be divided into aggressive (fast-growing) and indolent (slow-growing) types, and they can be formed from either B lymphocytes (B cells) or in lesser extent from T lymphocytes (T cells) or Natural Killer cells (NK cells). B-cell lymphoma makes up about 85% of non-Hodgkin’s lymphomas diagnosed in the US. Prognosis and treatment of non-Hodgkin’s lymphomas depend on the stage and type of disease.

On December 12, 2023 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of emavusertib (CA-4948), an orally available, small molecule IRAK4 inhibitor, reported initial combination study data from its TakeAim Lymphoma trial including 5 primary CNS lymphoma (PCNSL) patients (Press release, Curis, DEC 12, 2023, View Source [SID1234638489]).

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"We are very pleased with the initial emavusertib/ibrutinib combination data from the TakeAim Lymphoma study. We are particularly excited about the activity in relapsed/refractory PCNSL and the meaningful benefit emavusertib may provide in combination with BTKi," said James Dentzer, President and Chief Executive Officer of Curis.

As of October 12th, the TakeAim Lymphoma trial has enrolled and treated 19 Non-Hodgkin Lymphoma (NHL) patients, with a combination of emavusertib and ibrutinib; with emavusertib doses ranging from 100 mg to 300 mg BID. The initial data reveal encouraging efficacy, demonstrating multiple objective responses in both BTK-naïve and BTK-experienced patients.

Patients with PCNSL who had a history of failed BTKi therapy showed a particularly noteworthy response: 3 out of 5 evaluable PCNSL patients achieved a Complete Response (CR), with durability ranging from 0.3 – 8.9 months. These data underscore the potential of emavusertib to re-sensitize patients to BTKi therapy, marking a significant advancement in Non-Hodgkin Lymphoma treatment.

Consistent with our previous findings, the emavusertib/ibrutinib combination demonstrates a manageable and acceptable safety profile, with no observed dose-limiting toxicities (DLTs) in the 200 mg cohort and 2 reversible DLTs (stomatitis and syncope) in the 300 mg cohort.

About emavusertib (CA-4948)

Emavusertib is a small molecule IRAK4 inhibitor. IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with cancer. TLRs and the IL-1R family signal through the adaptor protein MYD88, which results in the assembly and activation of IRAK4, initiating a signaling cascade that induces cytokine and survival factor expression mediated by the NF-κB protein complex. Preclinical studies targeting IRAK1/4 in combination with FLT3 have demonstrated the ability to overcome the adaptive resistance incurred when targeting FLT3 alone. Further, emavusertib has shown anti-tumor activity across a broad range of hematologic malignancies including monotherapy activity in patient-derived xenografts and synergy with both azacitidine and venetoclax.

About TakeAim Lymphoma Study

TakeAim Lymphoma Study (NCT03328078) – study is open for enrollment.