On April 12, 2021 PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) ("PureTech" or the "Company"), a clinical-stage biotherapeutics company dedicated to discovering, developing and commercializing highly differentiated medicines for devastating diseases, reported the presentation of a scientific poster detailing additional promising preclinical results for its LYT-210 antibody at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Virtual Meeting (Press release, PureTech Health, APR 12, 2021, View Source [SID1234577926]).

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LYT-210 is a novel, fully human monoclonal antibody (mAb) directed against T cells bearing γδ1 receptors, which are known to suppress the anti-tumor immune response. The new research shared at AACR (Free AACR Whitepaper) demonstrates that LYT-210 is both highly specific and highly potent, rapidly inducing cell death of immune-suppressive γδ1 T cells, while sparing other T cells that play important roles in a healthy immune response. The research was conducted in vitro using both patient blood and cancer tissue. LYT-210 has potential as either a single agent or in combination with checkpoint inhibitors and other anti-cancer treatments.

"The role of γδ1 T cells in cancer immune suppression has come into sharp focus in recent years. We now know that these cells deploy multiple immunosuppressive signals to dampen the anti-tumor response and enable the cancer to grow and spread," said Aleksandra Filipovic, M.D. Ph.D., Head of Oncology at PureTech. "We are excited by these new data demonstrating that our LYT-210 therapeutic candidate can precisely target and swiftly deplete pathogenic γδ1 T cells. We believe that removing these culprits from the tumor microenvironment systemically may have the potential to reawaken the immune system and contribute to a strong anti-tumor response. Moreover, both we and others in the field have established that a heightened presence of pathogenic γδ1 T cells in tumor tissue and blood is correlated with more aggressive disease, poorer response to some therapies and a lower chance of survival. Given those links, we believe that the biomarker-centric approach we are developing as part of our γδ1 T cell program may have the potential to identify and select the patients who are most likely to benefit from LYT-210 in the clinic and beyond."

γδ1 T cells are upregulated in multiple solid tumors including breast cancer, glioblastoma, melanoma and pancreatic cancer. They suppress the immune response through multiple mechanisms, including blocking effector T cells, hindering antigen-presenting dendritic cells, restricting the anti-tumoral activity of γδ2 T cells and attracting tumor-associated macrophages and myeloid-derived suppressor cells to the tumor microenvironment. Pathogenic γδ1 T cells are distinct from cytotoxic γδ T cells, which are being used for adoptive T cell transfer or therapeutic engagement with bispecific antibodies. Depleting pathogenic γδ1 T cells has the capacity to modulate both innate and adaptive immunity, and their distinct phenotypic and functional properties make them excellent potential therapeutic targets.

On April 12, 2021 Flagship Biosciences, the leader in data-centric pathology and tissue analysis, and Leap Therapeutics (Nasdaq: LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, reported a partnership to use a clinically validated tumor expression assay utilizing RNAscope and tissue image analysis (Press release, Leap Therapeutics, APR 12, 2021, View Source [SID1234577942]). In a poster shared this week at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, the companies presented data on the validation of a Dickkopf-1 (DKK1) RNAscope chromogenic in situ hybridization (CISH) assay and digital image analysis solution.

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DKK1 is a secreted modulator of Wnt signaling that is frequently overexpressed in tumors and associated with a poor prognosis for patients. DKN-01 is a humanized monoclonal therapeutic antibody that binds to and blocks the activity of DKK1 and has demonstrated clinical activity in gastric/gastroesophageal junction (G/GEJ) adenocarcinoma patients with elevated tumoral expression of DKK1 RNA. The companies have demonstrated that the DKK1 RNAscope assay and accompanying digital image analysis solution is specific, sensitive, accurate and reproducible according to Clinical Laboratory Improvement Amendments (CLIA) guidelines. The assay is currently being applied to prospectively identify G/GEJ patients with elevated tumoral expression of DKK1 for treatment with a DKN-01 plus tislelizumab combination (Leap Therapeutics; NCT04363801).

"CISH assays can be used for the interrogation of clinical samples when protein targets are not sufficient," said Flagship Biosciences CEO, Trevor Johnson. "However, reading these assays can be challenging for pathologists. At Flagship, our pathologist-driven image analysis generates unique cellular data profiles that allow for the kind of robust quantitative solution that Leap was looking for. Using our proprietary image analysis technology and patented, cell-based tissue analysis, we deliver the data-rich tissue interpretations to support therapeutic development."

"This is a robust laboratory developed test (LDT) that is superior to traditional DKK1 immunohistochemistry (IHC) by demonstrating improved specificity and sensitivity," said Michael Kagey, Ph.D., Senior Director of Translational Medicine. "Furthermore, the use of the digital image analysis algorithm to quantify DKK1 signal and support pathologist interpretation is a novel approach that reduces the risk of scoring bias."

To select patients for their clinical study, Leap Therapeutics sends samples from the United States and the Republic of Korea to Flagship’s centralized laboratory. Flagship conducts the RNAscope assay, image analysis, data analysis, and in-house pathologist review, providing the information needed to make clinical trial enrollment decisions.

"The DKK1 RNAscope LDT is an integral component of our clinical development strategy," said Douglas E. Onsi, President and CEO of Leap Therapeutics. "The rapid sample turnaround time from Flagship has allowed for the prospective screening of patients to support enrollment. We look forward to our continued partnership with Flagship."

On April 12, 2021 Celldex Therapeutics, Inc. (Nasdaq:CLDX) reported the presentation of promising data from the Company’s growing bispecific platform at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 being held April 10th – 15th (Press release, Celldex Therapeutics, APR 12, 2021, View Source [SID1234577983]). The Company described the discovery and characterization of ILT4 inhibitory monoclonal antibodies (mAbs) for engineering bispecific antibodies (bsAbs) that revert myeloid cell suppression by antagonizing ILT4 and activate T-cell responses through PD-(L)1 inhibition (poster # 1865). Based on the results reported today, Celldex is developing clinical bispecific candidates that co-target ILT4 and PD-(L)1.

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Expression of ILT4 in several tumor types is associated with poor outcome. In preclinical models, antagonist antibodies to ILT4 have demonstrated immune enhancing and antitumor effects. More recently, in early clinical studies, combination approaches that combine co-targeting of ILT4 and checkpoint blockade have demonstrated clinical activity and safety, including in patients refractory to checkpoint inhibition therapy. The data Celldex presented at AACR (Free AACR Whitepaper) describe novel humanized antibodies with high affinity and specificity to ILT4 that effectively block immune suppression in macrophages. Candidate bispecific antibodies matched with either PD-L1 or PD-1 antibodies resulted in molecules that retained all the properties of the parental antibodies and simultaneously blocked the inhibitory signals from both ILT4 and PD-1. The data provide proof of concept for development of clinical candidates.

"Celldex continues to draw upon our deep antibody experience to build best-in-class bispecific antibodies to more effectively control antitumor immunity," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "The ILT4/PD-(L)1 approach combines two critical checkpoint pathways into one molecule, which may provide advantages from a development perspective and the potential for greater activity than the combination of the individual antibodies. We look forward to completing this work and selecting a lead candidate for advancement."

Celldex’s deep antibody experience and in-house manufacturing capabilities support efficient development of bispecific antibody targets. Targets are selected based on new science as well as their compatibility to be used in bispecific antibody formats with existing Celldex antibody programs. CDX-527, which combines CD27 activation and PD-1 blockade, was the first candidate to enter the clinic from the platform and is currently enrolling patients in a Phase 1 dose escalation study. Celldex is also exploring important targets controlling inflammation and auto-immune pathways.

On April 12, 2021 BriaCell Therapeutics Corp. (Nasdaq: BCTX, BCTXW) (TSX-V:BCT) ("BriaCell" or the "Company"), a clinical-stage biotechnology company specializing in targeted immunotherapies for advanced breast cancer, reported the presentation of results from clinical studies with its lead product candidate, Bria-IMT, summarized in a poster session held at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, a virtual meeting, held over two weeks (Week 1: April 10-15; Week 2: May 17-21) (Press release, BriaCell Therapeutics, APR 12, 2021, View Source [SID1234578327]).

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The findings indicate disease control in advanced breast cancer patients, including stable disease (SD), partial responses (PR) or complete responses (CR). Disease control was especially noted in patients with Grade I/II (i.e. well or moderately differentiated) tumors or those that matched Bria-IMT at 2 or more HLA alleles. Patients with low or undetectable levels of circulating cancer cells were more likely to benefit from therapy.

Patients were treated with the Bria-IMT regimen alone (i.e. monotherapy study) or the Bria-IMT regimen in combination with immune checkpoint inhibitors, including pembrolizumab (KEYTRUDA; manufactured by Merck & Co., Inc.), and, more recently, Incyte’s retifanlimab (INCMGA00012, under a corporate collaboration with Incyte Corporation). Dr. Bill Williams, BriaCell’s President & CEO, presented the results of the clinical and pathological analysis. The patient data summarized and discussed belong to previously disclosed patients (i.e., no incremental numbers enrolled).

Details and results on the poster presentation are summarized below:

Poster Title: Predictors of response to a modified whole tumor cell immunotherapy in patients with advanced breast cancer from two phase I/IIa trials

Analysis and Discussion:

• The Bria-IMT regimen with or without checkpoint inhibitors is able to induce an effective immune response and disease control in heavily pre-treated advanced breast cancer patients. The patients were all heavily pretreated and failed multiple prior regimens.
• Delayed Type Hypersensitivity (DTH) to Bria-IMT analysis identified a group with significantly higher rates of disease control and progression-free survival (8 months) in both monotherapy and combination therapy studies suggesting a robust immune response is predictive of clinical benefit in these patients.
• Highest levels of disease control and PFS was observed in patients who matched Bria-IMT at 2 or more HLA alleles in the monotherapy study but not in the combination therapy study supporting our strategy to develop Bria-OTS, an off-the-shelf personalized immunotherapy for advanced breast cancer.
• Patients with Grade I/II tumors (median of 8 prior therapy regimens) were more likely to respond with disease control (67%) and longer progression free survival. The response was more pronounced in the patients in the combination therapy study suggesting additive or synergistic effects of checkpoint inhibitors when combined with the Bria-IMT regimen. Bria-IMT, with a molecular signature most closely related to Grade I/II tumors, may result in disease control and clinical benefit especially in this subset of patients.

A copy of the poster is posted at the following: View Source

On April 12, 2021 Instil Bio, Inc. ("Instil") (Nasdaq: TIL), a clinical-stage biopharmaceutical company focused on developing tumor infiltrating lymphocyte, or TIL, therapies for the treatment of patients with cancer, reported that clinical data from a compassionate use program for the treatment of metastatic melanoma at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) virtual meeting April 10 – 15, 2021 (Press release, Instil Bio, APR 12, 2021, View Source [SID1234583990]). The presentation abstract and additional information is available on the AACR (Free AACR Whitepaper) conference web site at www.aacr.org.

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"Despite the recent advances in immunotherapy for solid tumors, many patients do not receive clinical benefit or experience relapse after an initial remission," said Robert Hawkins, MBBS FRCP, PhD, Chief Strategy Advisor to Instil and presenting study author. "In this compassionate use setting in which patients had exhausted all other available therapies, a one-time treatment with TILs was able to induce a remission in more than half of the treated patients."

"This presentation highlights the potential for ITIL-168 to produce deep and durable remissions in patients with advanced melanoma," said Bronson Crouch, Chief Executive Officer of Instil. "We eagerly anticipate beginning a global Phase 2 clinical trial investigating ITIL-168 for the treatment of advanced melanoma later this year."

In this compassionate use program, 21 patients with stage IV cutaneous melanoma were treated between 2011 and 2019 at the Christie Hospital in Manchester, United Kingdom with TILs manufactured by Instil. All TIL products were generated in Instil’s company-operated, in-house manufacturing facilities in Manchester.

Among the 21 patients, 14 (67%) achieved an objective response, with four (19%) achieving a complete response. All complete responders remained in remission at the time of data cutoff with those remissions ranging in duration from 30 months to over 80 months from TIL infusion. With a median duration of follow-up of 52.2 months, the median overall survival was 21.3 months with nearly half of patients experiencing long term survival. Side effects of treatment were largely transient, self-limited and generally attributable to the lymphodepleting chemotherapy regimen and post-TIL IL-2 treatment.

The company plans to submit these results for peer-reviewed publication in 2021.

Instil expects to begin a Phase 2 trial of ITIL-168 in advanced melanoma patients in the second half of 2021. The company anticipates obtaining topline safety and efficacy data in 2023, which could support the submission of a BLA to the FDA in 2023 and a Marketing Authorization Application to the European Medicines Agency in 2024.

Poster Information:

Title: Clinical Feasibility and Treatment Outcomes with Unselected Autologous Tumor Infiltrating Lymphocyte Therapy in Patients with Advanced Cutaneous Melanoma

Session Type: E-Poster Session

Session Title: Adoptive Cell Therapy

Abstract Number: LB150

About ITIL-168

ITIL-168 is an investigational, autologous cell therapy made from tumor infiltrating lymphocytes, or TILs. ITIL-168 is manufactured with Instil’s proprietary, optimized, and scalable manufacturing process, which has been designed to capture and preserve the maximum diversity of each patient’s TILs; the manufacturing process also offers significant scheduling flexibility for patients and physicians at the time of both tumor resection and TIL treatment. Instil plans to investigate ITIL-168 in a global phase 2 trial in advanced melanoma in 2021 and additional solid tumor indications in Phase 1 clinical trials beginning in 2022.