On June 22, 2020 Precigen, Inc., a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, reported preclinical data for its innovative investigational PRGN-3005 UltraCAR-T in patients with advanced, recurrent platinum resistant ovarian, fallopian tube or primary peritoneal cancer has been published as an e-poster and accompanying audio presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II (Press release, Precigen, JUN 22, 2020, View Source [SID1234561328]). The e-poster presentation titled PRGN-3005 UltraCAR-T: Multigenic CAR-T Cells Generated Using Non-viral Gene Delivery and Rapid Manufacturing Process for the Treatment of Ovarian Cancer (Abstract 6593) is part of the Immunology/Adoptive Cell Therapy session and is accessible on the AACR (Free AACR Whitepaper) e-poster website.

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Traditional methods for CAR-T cell manufacturing involve the use of viral vectors and ex vivo cell expansion at centralized manufacturing facilities, contributing to potentially high costs and extended waiting periods. Precigen’s UltraCAR-T platform, in contrast, is based upon a non-viral multigene delivery system combined with a rapid, decentralized manufacturing process without ex vivo expansion. Following isolation of the patient’s own T cells after blood draw, non-viral gene transfer occurs overnight at the medical center’s cGMP facility. The next day, UltraCAR-T cells are infused into the patient.

PRGN-3005 is an autologous CAR-T treatment simultaneously expressing three gene products, which results in a uniform, homogenous CAR-T cell therapy: 1) CAR to specifically target the unshed portion of Mucin 16 (MUC16), which is overexpressed on over 80% of ovarian tumors with limited expression found in healthy tissues; 2) membrane-bound IL-15 (mbIL15) to provide improved UltraCAR-T persistence and maintenance of preferred stem cell like memory phenotype; and 3) a kill switch to eliminate the CAR-T cells, if needed.

Preclinical data demonstrate the specificity and efficacy of using the rapidly manufactured PRGN-3005 UltraCAR-T cells for the treatment of ovarian tumors. Specifically, a single administration of PRGN-3005 showed significantly superior expansion and preferred memory phenotype of UltraCAR-T in vivo and significantly superior efficacy compared to traditional CAR-T resulting in all PRGN-3005 treated mice becoming tumor-free. Furthermore, rechallenging these tumor-free mice three months later with ovarian tumors for a second time (to simulate tumor relapse) led to the elimination of tumor burden without additional PRGN-3005 UltraCAR-T treatment. These data demonstrate the potential of UltraCAR-T cells to persist long-term in vivo, prevent CAR-T cell exhaustion, and mount a durable anti-tumor response with the ability to continue to respond upon tumor rechallenge.

"We are pleased to be able to share the preclinical data for PRGN-3005 that led to the IND clearance and initiation of the Phase I study," said Helen Sabzevari, PhD, President and CEO of Precigen. "Our preclinical results demonstrate that PRGN-3005 UltraCAR-T administered one day after non-viral gene transfer has superior anti-tumor efficacy and persistence compared to traditional CAR-T cells and represents a promising opportunity for ovarian cancer treatment. We look forward to sharing the first clinical data for PRGN-3005 in the second half of 2020."

Based on these preclinical results, the FDA approved the IND application, and the first-in-human PRGN-3005 Phase I clinical trial for advanced ovarian cancer is currently under way (clinical trial identifier: NCT03907527). The PRGN-3005 UltraCAR-T Phase I clinical study is an open-label, dose escalation study to evaluate the safety and maximal tolerated dose of PRGN-3005 UltraCAR-T delivered by intraperitoneal infusion (IP) or intravenous infusion (IV). The study population includes patients with advanced stage (III/IV) recurrent ovarian, fallopian tube, and primary peritoneal cancer who are platinum-resistant and have progressed after receiving standard-of-care therapies or are not eligible to receive available therapies with known clinical benefit.

About Ovarian Cancer
Worldwide, nearly 300,000 women are diagnosed with ovarian cancer every year1 with approximately 22,000 of them in the US2. Since early ovarian cancer is often without obvious symptoms, the disease is frequently diagnosed at an advanced stage where cancer has spread to distant parts of the body, such as the liver or lungs2,3. Five-year survival rates depend on stage and type of ovarian cancer with rates decreasing for advanced stage cancers that have spread to distant parts of the body3.

Precigen: Advancing Medicine with Precision
Precigen (Nasdaq: PGEN) is a dedicated discovery and clinical stage biopharmaceutical company advancing the next generation of gene and cell therapies using precision technology to target urgent and intractable diseases in our core therapeutic areas of immuno-oncology, autoimmune disorders, and infectious diseases. Our technologies enable us to find innovative solutions for affordable biotherapeutics in a controlled manner. Precigen operates as an innovation engine progressing a preclinical and clinical pipeline of well-differentiated unique therapies toward clinical proof-of-concept and commercialization. For more information about Precigen, visit www.precigen.com or follow us on Twitter @Precigen and LinkedIn.

Precigen’s UltraCAR-T Therapeutic Platform
Precigen’s UltraCAR-T platform has the potential to disrupt the CAR-T treatment landscape by increasing patient access through shortening manufacturing time, decreasing manufacturing-related costs, and improving outcomes using advanced approaches for precise tumor targeting and control of the immune system. The platform brings several key advancements: 1) Non-viral gene transfer using multigenic vectors for expression of multiple effector genes leads to better precision and control of tumor targeting and eliminates the need for virus; 2) Sustained persistence and desired phenotype of infused UltraCAR-T helps address T-cell exhaustion, a common issue with current CAR-T therapies; 3) T-cell control by incorporation of kill switch technology to potentially improve the safety profile; and 4) Rapid manufacturing of UltraCAR-T cells using our proprietary non-viral gene transfer process, which eliminates the need for ex vivo propagation, thus dramatically reducing wait times for patients from weeks to one day after gene transfer.

Trademarks
Precigen, UltraCAR-T, and Advancing Medicine with Precision are trademarks of Precigen and/or its affiliates. Other names may be trademarks of their respective owners.

On June 22, 2020 Silverback Therapeutics ("Silverback"), a biopharmaceutical company advancing a pipeline of therapies that are systemically delivered but locally active, reported that preclinical data for its lead ImmunoTAC candidate, SBT6050, will be presented at AACR (Free AACR Whitepaper) Virtual Annual Meeting 2020 Session II at 9:00 a.m. ET on June 22, 2020 (Press release, Silverback Therapeutics, JUN 22, 2020, View Source [SID1234561344]).

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The presentation, titled "SBT6050, a HER2-Directed TLR8 ImmunoTAC Therapeutic, is a Potent Human Myeloid Cell Agonist that Provides Opportunity for Single Agent Clinical Activity," shows that TLR8 agonism potently and uniquely activates human myeloid cells, driving a broad spectrum of anti-tumor immune mechanisms, including those not dependent on T cells.

In preclinical studies, SBT6050 activates human myeloid cells in the presence of HER2 expressing tumor cells, resulting in proinflammatory cytokine and chemokine production, inflammasome activation, and the indirect activation of cytolytic activity associated with T and NK cells. SBT6050’s functional profile was not replicated with conjugates comprised of TLR7-specific or resiquimod-derived agonists.

Robust, durable single agent activity is observed with the SBT6050 mouse surrogate in multiple tumor models, including those with low tumor infiltrating lymphocytes. In a human xenograft model lacking T, B, and NK cells, the SBT6050 mouse surrogate is curative as a single agent, demonstrating the ability of myeloid cells to mediate strong anti-tumor activity.

"TLR8’s robust expression and functional profile in human myeloid cells uniquely positions SBT6050 to potentiate anti-tumor responses through the activation of these innate immune cells present in tumors," said Valerie Odegard, Ph.D., Silverback’s chief scientific officer. "Our preclinical data highlight SBT6050’s potential to maximize anti-tumor immune responses, even in tumors lacking T cells. We are excited to be developing a much-needed immunotherapy for patients with HER2-expressing disease and will enter the clinic later this year."

On June 22, 2020 Kazia Therapeutics Limited (ASX: KZA;NASDAQ: KZIA), an Australian oncology-focused biotechnology company, reported to share poster presentations of interim data from the ongoing phase II study of paxalisib (formerly GDC-0084) in glioblastoma, the most common and most aggressive form of primary brain cancer, and from the phase I study of Cantrixil in ovarian cancer (Press release, Kazia Therapeutics, JUN 22, 2020, View Source [SID1234561360]).

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Key Points

Previous paxalisib data presented at ASCO (Free ASCO Whitepaper) was based on Stage 1 (n=9) of the ongoing phase II study in glioblastoma. This interim analysis at AACR (Free AACR Whitepaper) includes all patients in the study (n=30), and therefore provides a more robust and substantial data set
Progression-free survival (PFS) for paxalisib is 8.5 months, versus 8.4 months in the previous analysis
Paxalisib overall survival (OS) remains at 17.7 months, in line with ASCO (Free ASCO Whitepaper) data
A separate poster on the investigator-initiated study of paxalisib in combination with radiotherapy is presented by clinicians at Memorial Sloan Kettering Cancer Center in New York. It noted a ‘robust response’ in the first treated patient
Cantrixil data shows one complete response (CR) to treatment, meaning no measurable disease, and two partial responses (PR), for an overall response rate of 19% (3 / 16 evaluable patients)
Summary of Paxalisib Data in Comparison to Temozolomide (existing standard of care)

Temozolomide[1]
(FDA-approved treatment)

Paxalisib

(interim phase II data)

Progression-Free Survival (PFS)

5.3 months

8.5 months

Overall Survival (OS)

12.7 months

17.7 months

Kazia CEO, Dr James Garner, commented, "The data summarized in these posters help to strengthen our confidence in both our clinical programs. As paxalisib moves towards commencement of the GBM AGILE pivotal study in the second half of calendar 2020, these findings will be used to support set-up activities. In the meantime, the fact that the PFS has remained robust as the analysis is extended out to the full data set gives us a great deal of additional confidence in the efficacy signal it provides. For Cantrixil, the emergence of one complete responder (CR) to treatment is very positive, and these new results will help us to explore partnering opportunities over the second half of the year."

AACR Annual Meeting

The American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting is one of the leading global academic conferences for oncology research. It is typically attended by more than 20,000 clinicians, researchers, industry executives, and investors, representing over 140 countries. The conference is being conducted through a virtual format this year and has been broken into two sections. AACR (Free AACR Whitepaper) Virtual Meeting I took place 27-28 April 2020, and AACR (Free AACR Whitepaper) Virtual Meeting II is being held 22-24 June 2020.

The paxalisib poster is found under number CT205 (NCT03522298), and the Cantrixil poster under CT166 (NCT02903771). Registration to the virtual meeting is free and interested parties may register via the AACR (Free AACR Whitepaper) website. The posters can be viewed on our website:

View Source

View Source

Initial Data from Memorial Sloan-Kettering Study of Paxalisib with Radiotherapy

Dr Jonathan Yang and team at Memorial Sloan Kettering Cancer Center in New York, NY, also presented a poster (number CT252) on their ongoing phase I study of paxalisib in combination with radiotherapy (NCT04192981). The poster principally reported the design of their study, but also noted a ‘robust response’ in the first patient treated. Further data is expected as the study progresses

Next Steps

The paxalisb phase II study remains ongoing with a number of patients in follow-up and approximately half of the total enrolled patient population still receiving drug at the time of analysis. Kazia expects to complete the study in 1H CY2021.

Set-up work is well underway for paxalisib’s planned entry into the GBM AGILE pivotal study, and it is expected that the first patient will be enrolled in the second half of calendar 2020.

The Cantrixil phase I study is now complete and analysis is underway, with final data expected in the second half of calendar 2020.

On June 22, 2020 Shasqi, a leader in chemistry based locally-activated cancer drugs, reported data showing that the company’s lead candidate SQ3370 produced robust anti-tumor responses both at the target site and at distal lesions in a preclinical cancer model (Press release, Shasqi, JUN 22, 2020, View Source [SID1234561411]). The study, titled "SQ3370, a Local Activation Therapy of Cytotoxic Agents, Produces Sustained Responses in Target and Distal Lesions via Immune Activation," was presented in a poster with audio at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II.

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Shasqi’s SQ3370 is a novel investigational drug product that uses bioorthogonal "click" chemistry reactions to capture and activate an attenuated anthracycline prodrug at the target tumor site enabling higher doses of the cancer drug while reducing side effects commonly experienced with conventional chemotherapy. Unlike other therapeutic approaches, Shasqi’s technology is solely based on chemistry and is independent of tumor biology such as biomarker expression and enzymatic activity.

This new therapeutic modality can precisely control the duration of exposure and magnitude of activated drugs at a specific area in the body. This allows the exploration of therapeutic benefits of a drug that had been previously limited by existing routes of administration in the clinic (oral, intravenous, direct injection or controlled release).

"SQ3370 is powered by an innovative chemistry based approach to precisely deliver high doses of a cancer drug locally and potentially activate the immune system against human tumors, independent of biological markers," said Carolyn R. Bertozzi, Ph.D., professor of chemistry and HHMI investigator at Stanford University.

SQ3370 consists of two components – SQL70, a hyaluronic acid-based biomaterial and SQP33, a prodrug of Doxorubicin, a commonly used chemotherapy. During treatment, SQL70 biomaterial is first injected at the target tumor site. SQP33 prodrug is then given systemically through daily IV infusions for 5 days. SQP33 prodrug remains in attenuated form in the body until it reaches the target tumor site and is captured by SQL70. Once captured, SQP33 is converted and released as active Doxorubicin at the target tumor.

In the study, Shasqi’s scientists evaluated SQ3370 in a preclinical cancer model in mice bearing two tumors, where the target lesion was injected with the SQL70 biomaterial and the distal lesion was not.

Treatment with SQ3370 significantly prolonged overall survival by reducing target lesions compared to controls. Interestingly, SQ3370 also reduced tumor growth at the distal lesion, which was not injected with the SQL70 biomaterial. Together, this suggests SQ3370 can induce both local and systemic anti-tumor responses.

"Our data demonstrate that SQ3370 can significantly reduce tumor size in both, tumors injected with the biomaterial, and at distal lesions. The preclinical data suggests that our approach can be relevant against the critical challenges facing clinicians today: undetectable lesions or widely disseminated solid tumors," said Nathan Yee, Ph.D., Senior Scientist at Shasqi and an author of the study.

Immune biomarker analysis indicates that SQ3370 triggers an immune response as shown by an increase in cytotoxic and helper T cells, and a decrease in regulatory T cells in both target and distal lesions. To further validate the immune activating properties, combination treatment with SQ3370 and an immune-activating agent led to more robust and sustained anti-cancer responses than controls with conventional Doxorubicin.

Additionally, in a separate study in rats, SQ3370 reduced adverse exposure to heart, kidney and liver tissue compared to conventional Doxorubicin treatment, indicating lower off-target toxic effects.

"Because of its highly modular nature, we can use our platform on numerous cancer drugs with doses traditionally limited due to toxicity and uncover new pharmacological benefits," said José M. Mejía Oneto, M.D., Ph.D., Founder and CEO of Shasqi. "To evaluate the translation of our findings to humans, we are initiating our first clinical trial of SQ3370 as a monotherapy in advanced solid tumors, and expect to dose our first patient shortly."

The entire AACR (Free AACR Whitepaper) poster presentation plus an audio description of the data by Dr. Yee, can be found here. In addition, the abstract for the poster can be found here.

On June 22, 2020 Targovax ASA (OSE: TRVX), a clinical stage immuno-oncology company developing oncolytic viruses to target hard-to-treat solid tumors, reported 12-month efficacy and immunological data from the randomized phase I/II trial of ONCOS-102 in combination with standard of care chemotherapy in malignant pleural mesothelioma (MPM) (Press release, Targovax, JUN 22, 2020, View Source [SID1234564002]).

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The trial is an open label, exploratory phase I/II trial adding ONCOS-102 to standard of care (SoC) chemotherapy (pemetrexed/cisplatin) in first and second (and later) line MPM to assess safety, immune activation and clinical efficacy vs SoC only. In total, 31 patients have been treated in the trial, with 20 patients in the experimental group receiving the ONCOS-102 and SoC combination, and 11 patients in a control group receiving SoC only. The 31 patients have now completed the 12-month follow-up. The first set of data was reported in January 2020, see press release here, with an update in May 2020, see press release here.

The median Progression Free Survival (mPFS) for ONCOS-102 treated first line patients remains at 8.9 months, which is identical to the previously reported early data. mPFS for the control group first line patients treated with SoC chemotherapy only is 7.6 months. The first line mPFS data continues to compare favorably to SoC historical controls, which have shown mPFS of 5.7-7.3 months[1]. As there is now longer follow-up and few censored patients left in the PFS analysis, the updated figures can be considered close to final.

The 12-month survival rate was 64% in the first line ONCOS-102 treated patients, compared to 50% in the first line control group treated with SoC chemotherapy only (median Overall Survival is too early to report). The patients continue to be followed and updated Overall Survival (OS) figures will be published as they mature. This 64% 12-month survival rate is encouraging compared to the control group, but there are few historical control reference points. Recently, at ASCO (Free ASCO Whitepaper) 2020, results from a first line mesothelioma trial assessing SoC chemotherapy in combination with the anti-PD-L1 checkpoint inhibitor durvalumab showed a 70% 12-month survival rate. This suggests that ONCOS-102 alone plus SoC chemotherapy may already achieve a level of benefit close to that observed with checkpoint inhibition plus SoC chemotherapy. It is expected that addition of checkpoint inhibition to ONCOS-102 and Soc will provide even further clinical benefit due to engagement of distinct and complementary biological mechanisms. As such, Targovax’s future clinical development of ONCOS-102 will focus on first line mesothelioma with the triple combination of a checkpoint inhibitor, ONCOS-102 and SoC. A randomized phase II trial is currently being planned in collaboration with a pharma partner.

Tumor biopsy immunohistochemistry and gene expression analyses from the present trial confirm the predicted mode of action of ONCOS-102. Importantly, profound innate and adaptive immune activation is observed in the ONCOS-102 treated patients compared to the control group, and this immune activation is associated with better clinical outcome. The immune activation is hallmarked by an increase in intra-tumoral cytotoxic T-cells and upregulation of adaptive immunity and cytotoxicity related gene expression, in parallel with polarization from M2 to M1 macrophage phenotype and upregulation of PD-L1 expression, indicating that ONCOS-102 is driving a favorable remodeling of the tumor microenvironment. This powerfully demonstrates the immune activation potential of ONCOS-102 far beyond what is achieved by chemotherapy alone and suggests that patients may be effectively sensitized to treatment with an anti-PD1/L1 antagonist, thereby providing strong scientific rationale for the combination of ONCOS-102 and checkpoint inhibition in first line mesothelioma.

Dr. Magnus Jäderberg, Chief Medical Officer of Targovax, said: "We are very pleased to see the encouraging first line PFS data holding up in the 12-month analysis, with early signs of positive survival outcomes. We are particularly excited to observe a broad and profound immune activation in the ONCOS-102 treated patients, which confirms the proposed mode of action. ONCOS-102 treatment clearly drives a favorable remodeling of the tumor microenvironment, and this remodeling is linked to better clinical outcomes. This immune activated tumor micro-environment provides the key scientific rationale and an ideal backdrop for combination treatment with a checkpoint inhibitor. These data set us up perfectly to move forward with a trial combining ONCOS-102 and a checkpoint inhibitor, which we believe will release the full potential of immunotherapy in this hard-to-treat patient population".