On April 17, 2018 Elios Therapeutics, a biopharmaceutical company developing innovative particle-delivered, dendritic cell vaccines in oncology, reported initial open-label results from the ongoing Phase 2b clinical trial of the TLPLDC (tumor lysate, particle-loaded, dendritic cell) vaccine in patients with stage III and IV (resected) melanoma (Press release, Orbis Health Solutions, APR 17, 2018, View Source [SID1234529911]). Results were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting held April 14-18, 2018 in Chicago, Illinois.

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"We are encouraged by these initial open-label results from our Phase 2b trial which demonstrate a compelling safety profile and provide early evidence that the TLPLDC vaccine may enhance the efficacy of commonly used FDA-approved systemic therapies, including checkpoint inhibitors," said George E. Peoples, M.D., chief medical officer at Elios Therapeutics. "We look forward to continuing our assessment of the TLPLDC vaccine in this ongoing study as we evaluate opportunities for further clinical development of combination therapies."

In an ongoing prospective, randomized, double-blind, placebo-controlled Phase 2b trial, patients with resected Stage III and IV melanoma were randomized (2:1) to received either TLPLDC vaccine or placebo to prevent recurrence. All patients who recurred on the trial (met study endpoint) were then offered open-label TLPLDC along with standard of care therapy as determined by the patient’s treatment team.

The initial open-label results presented were from 22 patients. Seven patients had their recurrences resected and were treated with the TLPLDC vaccine to prevent a second recurrence. At 12.5 months of median follow-up, only one patient has recurred.

The remaining 15 patients were on a variety of FDA-approved systemic therapies for their non-resectable recurrences. Of these patients, two patients withdrew from the study and one was not treated. In the remaining 12 patients treated with the TLPLDC vaccine in combination with their standard of care systemic therapy, two patients had a complete response (median follow-up 8.6 months), seven had stable disease and two had progressive disease. One patient progressed initially on TLPLDC vaccine alone but was converted to a complete response once checkpoint inhibitor therapy was initiated. Importantly, the addition of the TLPLDC vaccine did not increase the toxicity of checkpoint inhibitors, BRAF/MEK inhibitors, or TVEC in these patients.

To view the full abstract, please visit the AACR (Free AACR Whitepaper) website at View Source

About TLPLDC
The TLPLDC (tumor lysate, particle-loaded, dendritic cell) vaccine is an autologous, personalized, therapeutic cancer vaccine designed to stimulate the immune system to recognize tumor cells and fight a patient’s specific cancer. TLPLDC is made from the patient’s own tumor cells and dendritic cells – the most potent antigen-presenting cells in the body. Once TLPLDC is injected, the tumor lysate-loaded dendritic cells present the tumor antigens to the immune system, stimulating the induction of tumor-specific, activated T cells that are able to find and destroy tumor cells that may remain in the body. TLPLDC is currently being studied as a monotherapy and in combination with standard of care checkpoint inhibitor therapy in a Phase 2b clinical trial for the treatment of late-stage melanoma at leading academic cancer centers in the United States.

Genprex has filed a 10-K – Annual report [Section 13 and 15(d), not S-K Item 405] with the U.S. Securities and Exchange Commission (Filing, 10-K, Genprex, 2018, APR 17, 2018, View Source [SID1234527531]).

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On April 17, 2018 Tocagen Inc. (Nasdaq: TOCA), a clinical-stage, cancer-selective gene therapy company, reported updated durable response data from the Phase 1 study involving patients with high-grade glioma who received Toca 511 & Toca FC at the time of surgical resection will be presented at the 2018 American Academy of Neurology (AAN) Annual Meeting and 2018 American Association of Neurological Surgeons (AANS) Annual Scientific Meeting. Previously disclosed clinical data will also be reviewed at these meetings (Press release, Tocagen, APR 17, 2018, View Source;p=RssLanding&cat=news&id=2342917 [SID1234525819]).

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Additionally, preclinical data describing the level of Toca 511 transduction required for an anti-tumor response will be presented at the 14th Annual PEGS: The Essential Protein Engineering Summit.

Details of the presentation at AAN, held April 21-27 in Los Angeles, are as follows. The full presentation will be placed on Tocagen’s website following the presentation.

Presentation Type: Oral presentation (Abstract: 1173)
Title: Toca 511 & Toca FC: Evaluation of durable response rate in the post-resection setting and association with survival in patients with recurrent high grade glioma
Presenter: Timothy Cloughesy, M.D., director of the University of California, Los Angeles, Neuro-Oncology Program
Date and Time: Tuesday, April 24, 2:00 p.m. – 2:12 p.m. PT

Details of the presentation at the AANS Annual Scientific Meeting, held April 28-May 2 in New Orleans, are as follows:

Presentation Type: Oral presentation (Abstract: 615)
Title: Evaluation of durable response rate in the post-resection setting and association with survival in patients with recurrent high grade glioma who received Toca 511 and Toca FC treatment
Presenter: Bob S. Carter, M.D., Ph.D., chief of the Massachusetts General Hospital department of neurosurgery
Date and Time: Tuesday, May 1, 11:32 a.m. – 11:42 a.m. CT

Details of the presentation at PEGS, held April 30-May 4 in Boston, are as follows. The full presentation will be placed on Tocagen’s website following the presentation.

Presentation Type: Oral presentation
Title: Replicating retroviruses for manipulation of the tumor immune ecosystem: preclinical and clinical outcomes
Presenter: Douglas Jolly, Ph.D., executive vice president of research and pharmaceutical development at Tocagen
Date and Time: Tuesday, May 1, 8:30 – 9:00 a.m. ET

About Toca 511 & Toca FC

Tocagen’s lead product candidate is a two-part cancer-selective immunotherapy comprised of an investigational biologic, Toca 511, and an investigational small molecule, Toca FC. Toca 511 is a retroviral replicating vector (RRV) that selectively infects cancer cells and delivers a gene for the enzyme, cytosine deaminase (CD). Through this targeted delivery, infected cancer cells carry the CD gene and produce CD. Toca FC is an orally administered prodrug, 5-fluorocytosine (5-FC), which is converted into an anti-cancer drug, 5-fluorouracil (5-FU), when it encounters CD. 5-FU kills cancer cells and immune-suppressive myeloid cells in the tumor microenvironment resulting in anti-cancer immune activation and subsequent tumor killing.

On April 17, 2018 Torque, an immuno-oncology company developing Deep Primed cellular therapies with pharmacologic control to direct immune power deep within the tumor microenvironment, reported preclinical data for the company’s Deep-Primed IL-15 and Deep-Primed IL-12 programs demonstrating their activity compared to systemically administered IL-15 and IL-12 (Press release, Torque Therapeutics, APR 17, 2018, View Source [SID1234525537]). These data were presented at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago.

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Torque is developing a new class of Deep-Primed immune cell therapeutics to dramatically expand cell therapy cures for cancer. Deep-Priming uses advanced material engineering to anchor immune-stimulatory drugs directly to the surface of multi-targeted, antigen-primed T cells to activate both the adaptive and innate immune system with pharmacologic control in the tumor microenvironment. This approach does not require genetic engineering and enables tunable loading of precise doses of cytokines onto the surface of T cells to deliver sustained and controlled immune activation.

"Both Il-15 and IL-12 are potent cytokines capable of inducing strong anti-tumor immune responses, yet their clinical use as systemic therapies is limited by the potential for severe toxicities," said Thomas Andresen, PhD, Chief Scientific Officer of Torque. "Anchoring these powerful immune activators to the surface of T cells that traffic to tumors is a unique approach to direct immune power in the tumor microenvironment. These preclinical studies demonstrate superior efficacy for this approach compared to systemic administration of these same cytokines and are the foundation for the first clinical trials that will begin later this year for Deep IL-15."

Highlights of the three preclinical presentations follow, and copies of the posters are available for download on the Torque website: https://bit.ly/2FZtPOW

Abstract 3575 / Poster 13: "Cell therapy with surface-tethered IL-12 provides immune system priming and strong anti-tumor activity"
Presenter: Jon Nardozzi, PhD, Torque; Session: Adoptive Cell Therapy 3
Key findings from the study:

Deep IL-12 Priming technology enables high loading of IL-12 doses on the surface of tumor-specific T cells.
Deep IL-12 Priming substantially increases tumor killing survival with adoptively transferred tumor-specific T cells in an aggressive solid tumor model and is superior to systemically administered IL-12.
Administration of repeat doses of Deep IL-12 Primed T cells without pre-conditioning (lymphodepletion) further increases tumor killing and survival with adoptively transferred T cells in this aggressive solid tumor model.
Deep IL-12 Primed T cells activate an endogenous immune response but do not induce overt toxicities such as weight loss or sustained systemic cytokine release.
Abstract 3577 / Poster 15: "Deep IL-15 provides autocrine stimulation and expansion of autologous T cells driven by controlled concentrated release of IL-15"
Presenter: Pengpeng Cao, PhD, Torque; Session: Adoptive Cell Therapy 3
Key findings from the study:

Deep IL-15 Priming technology loads IL-15 on T cells with a highly controlled dose per cell and provides slow release of IL-15 for autocrine stimulation and sustained adoptive T cell therapy expansion.
In contrast to systemically delivered IL-15, Deep IL-15 substantially increases target CD8 T cell concentration in the tumor, without significant systemic IFNg levels or endogenous CD8 and NK cell expansion, due to lack of systemic exposure.
Torque’s fully closed manufacturing process that uses a proprietary dendritic cell priming process generates several billion, antigen-primed human T cells with an average of 20% reactivity and >95% T cell purity (demonstrated with autologous cells from healthy human donors).
Clinical trials using this manufacturing process for Deep IL-15 Primed multi-target T cells are expected to initiate in 2018.

Also at AACR (Free AACR Whitepaper), the Irvine Lab of the Koch Institute at MIT presented data on IL-12 and IL-15 formulated in nanogels and anchored to T cells using technology developed in the Irvine Lab. Torque has built upon the Irvine Lab’s work to create the Deep-Priming technology platform. The Irvine Lab is directed by Darrell Irvine, PhD, who is a co-founder of Torque and Chairman of Torque’s Scientific Advisory Board, Professor at the Massachusetts Institute of Technology, and an Investigator of the Howard Hughes Medical Institute.

Abstract 3565 / Poster 3: "T cell receptor signaling-responsive single chain IL-12 and IL-15 superagonist nanogel ‘backpacks’ to enhance adoptive cell therapy in solid tumors"
Presenter: Michael Fichter, PhD, Koch Institute for Integrative Research at MIT; Session: Adoptive Cell Therapy 3
Key findings from the study:

IL-15 nanogels anchored to tumor-targeted T cells induces significant and specific expansion of the adoptively transferred T cells in tumors and lymph nodes that is superior to systemic IL-15.
IL-15 nanogels anchored to T cells substantively improved the efficacy of an adoptive T cell therapy against solid tumors while reducing cytokine-induced side effects triggered by systemically administered IL-15.
In a separate experiment, IL-12 nanogels anchored to CD8 effector cells induced substantial cell activation.
About Deep-Primed Immune Cell Therapeutics
Torque’s Deep-Priming platform is based on 10 years of research and development to combine very potent immunomodulatory drugs with T cells to drive a powerful immune response with pharmacologic control in the tumor microenvironment. We are developing Deep-Primed T cells using a focused set of immunomodulators—initially IL-15, IL-12, and TLR agonists—that activate both innate and adaptive immunity. Administering these immunomodulators systemically to a patient can cause lethal toxicity by activating immune cells throughout the body. Deep-Primed therapeutics are designed to activate T cells and focus the immune response to target the tumor, without systemic exposure. This is achieved by:

Anchoring the immunomodulators to the surface of T cells to activate and direct the immune response in the tumor microenvironment
Modular antigen priming of T cells to target multiple, tumor-associated antigens using a proprietary cell-processing technology
In hematologic cancers, this new class of immune therapeutics has the potential to improve on the initial success of single-target CAR-T therapeutics. For solid tumors, Deep-Primed T-cells have the potential to enable efficacy against tumors with heterogeneous antigens protected by hostile microenvironments, which are not readily addressable with the first generation of immune cell therapies.

On April 17, 2018 GRAIL, Inc., a life sciences company focused on the early detection of cancer, reported initial results from its Circulating Cell-Free Genome Atlas (CCGA) Study (Press release, Grail, APR 17, 2018, View Source [SID1234525517]). Data from three prototype genome sequencing assays showed it may be feasible to develop a blood test for early detection of multiple cancer types with greater than 99 percent specificity.

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"We are excited that early results with our prototype assays suggest we can develop blood tests for early detection of cancer with a very low rate of false-positive results," said Alexander Aravanis, MD, PhD, Vice President of Research and Development at GRAIL. "These data will be used to inform development of a blood test for early detection of multiple cancer types. Our next steps are to analyze additional data sets from CCGA, including validating these results in an independent data set, and to continue optimizing our assays."

The data were presented today by Dr. Aravanis in a late-breaking research minisymposium at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago (Abstract LB-343).

Specificity Analyses

When developing early detection tests, high specificity is important to minimize false-positive results. Across all three of the assays evaluated, a "cancer-like" signal was found in less than one percent of participants who entered the study without a cancer diagnosis (5 of 580), suggesting a test with a specificity greater than 99 percent is feasible. Through longitudinal follow-up in the study, it has since been confirmed that two of the five participants who had a cancer-like signal have been diagnosed with cancer. This suggests the signal indicated presence of undiagnosed cancer. Follow-up of the other three participants continues.

Clonal hematopoiesis of indeterminate potential (CHIP) is a known confounding signal present in cell-free DNA (cfDNA) of white blood cells that could increase false-positive results. This CHIP signal is likely due to natural aging processes. Therefore, in this study, paired sequencing of white blood cells and cfDNA was performed to identify these non-cancer mutations. Somatic (non-inherited) mutations from the white blood cells accounted for 66 and 78 percent of all mutations identified in participants with and without cancer, respectively.

Sensitivity Analyses

Initial analyses showed all three prototype assays detected a strong biological signal in cancer types that are typically not screened for and have low survival rates (five-year cancer-specific mortality rate of greater than 50 percent1). These included lung, ovarian, pancreatic, liver, and esophageal cancers. The signal was detected across all stages of cancer, and increased with stage across all three of the assays. The assays evaluating the whole genome performed best, and the whole-genome bisulfite assay showed the strongest detection rates. Additional data showing detection rates for specific cancer types will be presented at an upcoming medical meeting.

In this pre-planned sub-study of CCGA, three prototype sequencing assays were evaluated as potential methods for a blood-based test for early cancer detection. Blood samples from 878 participants with newly diagnosed cancer who had not yet received treatment and 580 participants without diagnosed cancer were sequenced with all three prototype assays. Twenty different cancer types across all stages were included in the sub-study.

The prototype sequencing assays included:

Targeted sequencing of paired cfDNA and white blood cells to detect somatic mutations such as single nucleotide variants and small insertions and/or deletions;
Whole-genome sequencing of paired cfDNA and white blood cells to detect somatic copy number changes; and
Whole-genome bisulfite sequencing of cfDNA to detect abnormal cfDNA methylation patterns.
About CCGA

CCGA is a prospective, observational, longitudinal study designed to characterize the landscape of cell-free nucleic acid (cfNA) profiles in people with and without cancer. The planned enrollment for the study is more than 15,000 participants across 141 sites in the United States and Canada. Approximately 70 percent of participants will have cancer at the time of enrollment (newly diagnosed, have not yet received treatment) and 30 percent will not have a known cancer diagnosis. The groups are demographically similar and representative of a real-world population. The group of participants without cancer includes individuals with conditions that are known to increase cfNA signal, such as inflammatory or autoimmune diseases. Planned follow-up for all participants is at least five years to collect clinical outcomes.

Presentation Details
Abstract LB-343

Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas (CCGA)

Alexander M. Aravanis et al. Tuesday, April 17, 2018: 4:20-4:35pm CDT, Session LBMS01 – Minisymposium: Late-Breaking Research, Room S101 – McCormick Place South (Level 1).