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HotSpot Therapeutics Presents Preclinical Data from CBL-B Program at 2022 Society for Immunotherapy of Cancer Annual Meeting

On November 10, 2022 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of orally delivered, small molecule allosteric therapies for the treatment of cancer and autoimmune diseases, reported the presentation of additional preclinical data on the Company’s Casitas B-lineage lymphoma proto-oncogene (CBL-B) program in two poster presentations at the 2022 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (Press release, HotSpot Therapeutics, NOV 10, 2022, View Source [SID1234623866]).Due to its role as a gatekeeper in immune cell activation, CBL-B inhibition holds the potential to address several key mechanisms important in immuno-modulation. Translational data supports a role for CBL-B inhibition to address suboptimal response to current immunotherapies in certain cancers. Targeting CBL-B represents a novel therapeutic approach because inhibition of CBL-B has been shown to lower the threshold for T cell and NK cell activation, even in the absence of co-stimulatory signals, potentially bringing benefit to patients with suboptimal conditions in the tumor microenvironment.

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"At HotSpot, we are generating preclinical data elucidating the central role of CBL-B inhibition to immune cell activation, providing strong biological rationale for this mechanism’s potential as a promising immuno-oncology treatment option," said Geraldine Harriman, Ph.D., Co-Founder and Chief Scientific Officer of HotSpot Therapeutics. "Our data in syngeneic mouse models underscore the broad range of immunostimulatory activity of CBL-B inhibition which, coupled with compelling data from the mixed lymphocyte reaction (MLR) assay, a clinical correlate for I-O agents, as well as clear synergistic activity with anti-PD-1, support the continued advancement of our CBL-B inhibitor program. We look forward to continuing to work toward advancing HST-1011, our lead CBL-B inhibitor development candidate, into the clinic."

The presentations describe compelling data for HotSpot compounds designed as novel, allosteric, small molecule inhibitors of CBL-B E3 ubiquitin ligase activity:

A HotSpot CBL-B inhibitor demonstrated immune-mediated tumor growth inhibition in multiple syngeneic mouse models. Gene expression profiling of the tumor microenvironment demonstrated upregulation of pro-inflammatory pathways in vivo. These effects were notable with CBL-B inhibition alone and further enhanced when combined with a PD-1 inhibitor.
In the MLR assay, a predictive correlate of the clinical activity of I-O therapies, the HotSpot CBL-B inhibitor demonstrated robust effects on cytokine release and T cell proliferation as monotherapy. Additionally, CBL-B inhibition demonstrated synergistic activity in the MLR assay when combined with anti-PD1.

Nektar Therapeutics Presents Preclinical Data from Novel PEGylated Interferon Gamma Program, NKTR-288, at the Society for Immunotherapy of Cancer (SITC) Annual Meeting

On November 10, 2022 Nektar Therapeutics (Nasdaq: NKTR) reported the first presentation of preclinical data for NKTR-288 at the 2022 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (Press release, Nektar Therapeutics, NOV 10, 2022, View Source [SID1234623865]).

NKTR-288 is a novel polyethylene glycol (PEG)-conjugate of interferon gamma (IFN-γ), designed to modify binding of IFN-γ to its substrates and optimize the duration of IFN-γ signaling. IFN-γ is a cytokine that induces cellular antigen presentation and enhances tumor antigen-specific cytotoxic T cell response, and may have applications in a number of therapeutic areas, including oncology and infectious diseases, among others.

The presentation today showed the sustained pharmacological properties of NKTR-288 relative to native cytokine, including durable exposure and induction of the well characterized interferon gamma response. These data support further evaluation of NKTR-288 as a monotherapy or in combination with checkpoint inhibitors in the clinical setting.

"The results presented at SITC (Free SITC Whitepaper) clearly demonstrate that NKTR-288 has differentiated pharmacokinetic and pharmacodynamic properties compared to native IFN-γ, leading to durable in vivo anti-tumor activity in preclinical models," said Jonathan Zalevsky, Ph.D., Senior Vice President and Chief Research & Development Officer at Nektar. "Particularly promising were data that show NKTR-288 upregulates PD-L1 expression in tumor tissue, supporting potential combination therapy with checkpoint inhibitors by enhancing checkpoint blockade efficacy in low-MHC Class I ‘cold’ tumor models. It highlights the potential of NKTR-288 to augment currently available PD-1 or PD-L1 treatment strategies and possibly broaden the responsive patient population."

Also presented at SITC (Free SITC Whitepaper) by Nektar’s partner, Merck KGaA, is a trials in progress poster of the Phase 2 JAVELIN Bladder Medley study (NCT05327530). The ongoing clinical trial includes evaluation of BAVENCIO (avelumab), Merck’s anti-PD-L1 therapy, in combination with NKTR-255, Nektar’s IL-15 receptor agonist designed to increase the proliferation and survival of natural killer (NK) cells and memory CD8+ T cells to enhance anti-tumor immunity. Merck KGaA is running this study and is on track to generate comparative progression-free survival (PFS) data for this study by the end of 2024.

Key details and takeaways from the presentation are as follows:

Abstract 1086: "NKTR-288, a PEGylated Interferon Gamma Drug Candidate for the Treatment of Cancer", Hamel, D., et al.

NKTR-288 demonstrated reduced affinity to both IFN-γ receptor and heparin, decreasing target mediated drug disposition (TMDD) and increasing bioavailability compared to native IFN-γ.
Induced sustained upregulation of major histocompatibility complex class I (MHC Class I) expression in fast-growing, low-MHC Class I "cold" syngeneic tumor models, as well as T cell-mediated anti-tumor activity, alone and in combination with checkpoint inhibitors.
NKTR-288 also upregulated PD-L1 expression in tumor tissue as a monotherapy, while significant anti-tumor activity was observed when combined with anti-PD-1 or anti-PD-L1 antibodies.
Well tolerated at pharmacologically active doses in preclinical models well below maximum tolerated dose (1 mg/kg).
These results support the development of NKTR-288, a novel, optimized IFN-γ pathway agonist, to treat cancer as a monotherapy or in combination with PD-1/PD-L1 therapy.
Details of the Trials in Progress poster presentation are as follows:

Abstract 665: "JAVELIN Bladder Medley: a phase 2 trial of avelumab in combination with other antitumor drugs as first-line maintenance therapy for advanced urothelial carcinoma", Hoffman-Censits, J., et al.

The objective of the phase 2, multicenter, randomized, open-label parallel-arm JAVELIN Bladder Medley umbrella trial (NCT05327530) is to assess the safety and efficacy of avelumab in combination with other antitumor agents, including NKTR-255, as first-line (1L) maintenance treatment for patients with advanced urothelial carcinoma (UC).
When completed, the ongoing JAVELIN Bladder Medley study will show whether 1L maintenance treatment with avelumab-based combinations can improve PFS vs avelumab alone and report the safety and tolerability of the combination regimens.
Details of the data presentations at SITC (Free SITC Whitepaper) are available on the Science section of Nektar’s website at View Source

About NKTR-288

NKTR-288 is a PEG-conjugate of the protein, IFN-γ, a cytokine that induces cellular antigen presentation and has great potential in cancer treatment through enhancement of tumor antigen specific cytotoxic T cell response. NKTR-288 was designed utilizing a site-specific conjugation approach to modify binding of IFN-γ with one of its substrates, and overall, to optimize the duration of IFN-γ signaling. This program has applications in a number of therapeutic indications including oncology as well as in infectious disease and others.

About NKTR-255

NKTR-255 is a biologic that targets the IL-15 pathway in order to activate the body’s innate and adaptive immunity. Through optimal engagement of the IL-15 receptor complex, NKTR-255 is designed to enhance functional NK cell populations and formation of long-term immunological memory, which may lead to sustained and durable anti-tumor immune response.

Preclinical findings suggest NKTR-255 has the potential to synergistically combine with antibody-dependent cellular cytotoxicity molecules as well as to enhance CAR-T therapies. Nektar has initiated a Phase 1 dose escalation and expansion clinical study of NKTR-255 in adults with relapsed or refractory non-Hodgkin lymphoma or multiple myeloma, as well as a Phase 1/2 clinical study of NKTR-255 in patients with relapsed or refractory head and neck squamous cell carcinoma or colorectal cancer. Nektar is also continuing its oncology clinical collaboration with Merck KGaA and Pfizer Inc. to evaluate the maintenance regimen of NKTR-255 in combination with avelumab, a PD-L1 inhibitor, in patients with locally advanced or metastatic urothelial carcinoma in the Phase 2 JAVELIN Bladder Medley study. Nektar is also currently designing a Nektar-sponsored Phase 2/3 study combining NKTR-255 with approved CAR-T cell therapies in diffuse large B-cell lymphoma, which it aims to initiate in the first quarter of 2023.

Corbus Presents Latest Preclinical Data for CRB-601 at the Society for Immunotherapy of Cancer (SITC) 37th Annual Meeting

On November 10, 2022 Corbus Pharmaceuticals Holdings, Inc. (NASDAQ: CRBP) ("Corbus" or the "Company"), an oncology company, reported that it is presenting new preclinical data for CRB-601 in a poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in Boston (Press release, Corbus Pharmaceuticals, NOV 10, 2022, View Source [SID1234623864]).

The latest preclinical data demonstrate significant tumor growth inhibition by CRB-601 as a single agent and in combination with anti-PD-1 treatment in the syngeneic murine tumor models MC38 and EMT6. In addition, treatment with CRB-601 appears to restore sensitivity to checkpoint inhibitors in the Pan02 and 4T1 syngeneic tumor models, regarded as "desert" tumors that are non-responsive to current CPIs. CRB-601 is the only anti-αvβ8 targeting agent known to demonstrate such an effect in these models to date.

The anti-tumor effects in the immune excluded EMT6 model correlated with changes in the immune cell populations in the tumor microenvironment. There were increases in proliferating CD4+ and CD8+ T-cells and Natural Killer cells, and a shift in macrophage polarization to the inflammatory M1 phenotype. Collectively these data suggest that treatment with CRB-601 could address tumors with an immune excluded phenotype, as represented by this model, and facilitate sensitization to anti-PD-1 therapy.

Additionally, tumor protection is associated with a durable T-cell memory response. Tumor-bearing mice initially rendered tumor-free by treatment with the combination of CRB-601 + anti-PD-1 were subsequently reinoculated with the same tumor cells (MC38) and monitored for tumor establishment and growth. After 30 days no tumors had formed in this cohort of animals, whereas implantation and eventual death occurred in 100% of the treatment naïve control animals. T-cell depletion studies indicated that protection against MC38 tumor growth in these rechallenged animals was dependent upon CD8+ T-cells.

"CRB-601 demonstrates robust pre-clinical anti-tumor activity alone and in combination with anti-PD-1 therapy in tumors exhibiting a range of sensitivities to anti-PD-1 therapy. The ability of CRB-601 to significantly reduce the growth of tumors that are non-responsive to CPIs and to sensitize these tumors to CPI therapy continues to support our hypothesis that effective blockade of latent TGFβ activation should lead to enhanced immune cell invasion in the tumor microenvironment and augment the effects of anti-PD-1 therapy. The increased activity of CRB-601 in tumors expressing αvβ8 provides a promising biomarker for patient selection and stratification," commented Rachael Brake, Ph.D., Chief Scientific Officer of Corbus.

Corbus is currently developing CRB-601 as a potential treatment for solid tumor cancers, and the program is on schedule for an IND submission in mid-2023.

Dr. Daqing Wang, PhD will be presenting the new data today in Poster #815 in Hall C from 11:40 am – 1:10 pm and again from 7:30 pm – 9 pm. The SITC (Free SITC Whitepaper) poster is available on the company website at: View Source

Regen BioPharma Developing a Non-Exhaustible CAR-T Cell Therapeutic

On November 10, 2022 Regen BioPharma, Inc. (OTC PINK: RGBP) and (OTC PINK: RGBPP) reported that it has recently discussed the use of CAR-T therapies in cancer treatment (View Source;explores-the-car-t-therapeutic-space-301660078.html) and its development of a novel approach to creating CAR-T cells that can potentially be used to treat solid tumors (View Source;develops-novel-dedifferentiation-approach-for-increasing-efficacy-of-car-t-cells-to-treat-solid-tumors-301604599.html).

The tumor microenvironment contains molecules and cells which can suppress T cells and prevent them from attacking and killing the tumor. "T cell exhaustion" is a term that describes T cells that are initially recruited to a tumor to kill it but end up rapidly losing their effectiveness. Eventually the tumor is surrounded by T cells that are exhausted and ineffective.

The Company has focused on NR2F6, an immune checkpoint which has been convincingly shown to be a very important transcription factor that keeps T cells in check1-4. When this transcription factor is blocked, T cells become very active and can kill tumors much more effectively. The Company has coupled its proprietary shRNA technology, which inhibits NR2F6, with existing CAR-T cell technology to create a potentially durable CAR-T cell which cannot be exhausted by the solid tumor microenvironment. The Company calls this novel CAR-T cell DuraCAR.

"We believe DuraCAR has the characteristics to overcome several of the major hurdles in getting CAR-T cells to be effective in treating solid tumors," says Dr. David Koos Chairman and CEO of the company. "We will know more in the coming months from our experimental work how long the road will be to get our technology fine-tuned to the point where we have a proof-of-concept drug. It is very exciting to see our shRNA technology applied in a way that can potentially help so many people with cancer."

1Klepsch et al. Targeting the orphan nuclear receptor NR2F6 in T cells primes tumors for immune checkpoint therapy Cell Communication and Signaling (2020) 18:8. View Source

2Klepsch, V., Hermann-Kleiter, N., Do-Dinh, P. et al. Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade. Nature Communications (2018) 9, 1538. View Source

3Klepsch et. al. Beyond CTLA-4 and PD-1: Orphan nuclear receptor NR2F6 as T cell signaling switch and emerging target in cancer immunotherapy. Immunology Letters (2016) 178, 31-36. View Source

4Hermann-Kleiter, et. al. The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance. Cell Reports (2015) 12:12, 2072-2085. View Source

QUE Oncology’s non-hormonal therapy reduces hot flushes and night sweats in women with breast cancer, published in The Lancet

On November 10, 2022 QUE Oncology reported the results of its Phase II trial of Q-122, a novel non-hormonal oral therapy for the treatment of vasomotor symptoms (commonly known as hot flashes/flushes and night sweats) in women taking endocrine therapy for breast cancer, have been published in The Lancet (Press release, QUE Oncology, NOV 10, 2022, View Source [SID1234623861]).

More than 75 per cent of breast cancers are hormone-sensitive, with endocrine therapy being the standard treatment option[1]. Endocrine therapy is recommended for 5-10 years after cancer treatment for those women that had hormone-sensitive breast cancer, to prevent disease recurrence. However, approximately 70 per cent of women taking endocrine therapy have vasomotor symptoms that contribute to over one third of women prematurely stopping this important therapy.

The Phase II study was a multicentre, randomised, double-blind, placebo-control trial involving 131 women taking endocrine therapy (tamoxifen or an aromatase inhibitor) following breast cancer.

Q-122 therapy significantly reduced the frequency and severity of moderate and severe vasomotor symptoms, with associated improvement in quality of life, compared with placebo. Q-122 was well tolerated with no serious adverse effects. These results demonstrate the promise of Q-122 as a novel and differentiated, non-hormonal treatment of vasomotor symptoms for women with breast cancer taking endocrine therapy, and the potential for its use in post-menopausal women experiencing similar symptoms.

"Our research findings published in The Lancet demonstrate efficacy of Q-122 as a non-hormonal oral treatment for vasomotor symptoms in women taking oral adjuvant endocrine therapy after breast cancer, with no evidence of treatment side effects," explains Principal Investigator and Senior Author, Professor Susan Davis Director, of the Monash University Women’s Health Research Program.

"In addition to a reduction in flushes and sweats, women who received Q-122 in the study reported a significantly lower likelihood of their hot flushes and sweats interfering with their sleep, and social and leisure activities, compared with placebo. If Q-122 can provide relief from these symptoms, it holds great potential for reducing discontinuation of endocrine therapy, enabling ongoing protection against breast cancer recurrence. This is an extremely important potential benefit of Q-122 beyond symptom relief alone," Professor Davis added.

QUE Oncology was formed through a joint venture between Emory University in Atlanta and the University of Queensland (UQ) research commercialisation company, UniQuest. The company has been supported by leading life science investors, including the Brandon Capital-managed Brandon BioCatalyst and Uniseed.

"It’s great to see extremely positive results from QUE Oncology’s Phase II trials published in the world’s leading independent general medical journal. The research highlights the need for a therapy for patients undergoing endocrine therapy for breast cancer who are experiencing vasomotor symptoms, but also the broader potential for Q-122 beyond this patient group, including postmenopausal women, of which 70-80 per cent experience vasomotor symptoms," says Dr Chris Nave, Chairman of QUE Oncology and CEO of Brandon BioCatalyst.

The results of QUE Oncology’s Phase II study support the conduct of larger and longer studies of Q-122, with potential use extending to postmenopausal women who require an alternative to oestrogen therapy for vasomotor symptoms.

[1] Bell RJ, Fradkin P, Schwarz M, Davis SR. Understanding discontinuation of oral adjuvant endocrine therapy by women with hormone receptor positive invasive breast cancer nearly 4 years from diagnosis. Menopause. 2013 Jan;20(1):15-21

ENDS

Q-122 Phase 2 study:

Eligible participants were women, aged 18–70 years, taking a stable dose of tamoxifen or an aromatase inhibitor following breast cancer and experiencing at least 50 self-reported moderate to severe vasomotor symptoms per week.

Participants were randomly assigned (1:1) using an interactive web response system to oral Q-122 100 mg or identical placebo, twice daily for 28 days. Randomisation was stratified by BMI (≤30 kg/m² or >30 kg/m²) and use of any of a selective serotonin reuptake inhibitor, selective norepinephrine reuptake inhibitor, gabapentin, or pregabalin.

Between Oct 24, 2018, and Sept 9, 2020, 243 patients were screened, 131 of whom were randomly assigned and received treatment (Q-122 n=65 and placebo n=66).

Q-122 resulted in a significantly greater mean percentage change in msVMS-SS from baseline over 28 days of treatment compared with placebo (least squares mean: Q-122, –39% [95% CI –46 to –31] vs placebo –26% [–33 to –18]; p=0・018).
Treatment-emergent adverse events were generally mild to moderate and similar between the two groups (treatment-related treatment-emergent adverse events in 11 [17%] of 65 patients in the Q-122 group vs nine [14%] of 66 in the placebo group); zero patients in the Q-122 group and two (3%) patients in the placebo group had serious adverse events.