The following is a roundup of presentations and findings from multiple companies participating in the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) in Chicago (Press release, BioSpace, APR 17, 2018, View Source [SID1234525435]).

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H3 Biomedicine Inc. – Working with Foundation Medicine, H3 Biomedicine unveiled novel findings from a comprehensive genomic analysis of 6,235 patients across 15 hematologic malignancies at AACR (Free AACR Whitepaper). The results include the first-ever observance of recurrent RNA splicing factor mutations in non-Hodgkin’s lymphoma and multiple myeloma, the company said. In its announcement, H3 said the findings demonstrate the "continued emergence of splicing factor mutations as a hallmark of dozens of hematologic and solid tumor cancers, their potential role in tumor formation and growth, and, thus, the opportunity to advance a new class of therapies."
Checkmate Pharmaceuticals – Data from an ongoing Phase Ib trial shows that Checkmate’s Toll-like receptor 9 CMP-001 combined with Merck’s Keytruda demonstrated "deep and durable clinical responses" in patients with advanced melanoma who are resistant to prior anti-PD-1 checkpoint inhibition. Data shows that the combination therapy brought about the systemic regression of "non-injected cutaneous, nodal, hepatic, and splenic metastases in patients who had progressed on a median of two prior therapies."

Deciphera Pharmaceuticals – Cambridge, Mass.-based Deciphera unveiled preclinical data that showed DCC-2618, a KIT and PDGFRα kinase switch control inhibitor, inhibited primary and secondary KIT mutations and primary PDGFRα mutations in gastrointestinal stromal tumors (GIST) and systemic mastocytosis. Deciphera said in comparison to other approved compounds, DCC-2618 demonstrated the "broadest profile of inhibition" in the preclinical study.
NewLink Genetics – In a poster presentation at AACR (Free AACR Whitepaper) NewLink showed that indoximod has a unique method of action in modulating AhR-driven transcription of genes. The company said the different mechanism of action may contribute to antitumor immune responses in the IDO pathway, as well as independent of that IDO pathway. The company said indoximod regulates the "differentiation of helper T cells toward an immuno-stimulatory helper function and downregulates genes that control the differentiation of T cells into immuno-suppressive regulatory T cells in an AhR dependent manner."

Torque – Preclinical data presented by Torque at AACR (Free AACR Whitepaper) shows the company’s Deep-Primed IL-15 and Deep-Primed IL-12 cellular therapy programs demonstrated superior activity compared to systemically administered IL-15 and IL-12. Torque’s Deep-Primed therapeutics use material engineering to anchor immune-stimulatory drugs directly to the surface of multi-targeted, antigen-primed T cells. This allows the activation of the adaptive and innate immune system with pharmacologic control in the tumor microenvironment, according to the company.
Laboratory for Advanced Medicine – With a push to advance early cancer diagnostics California-based Laboratory for Advanced Medicine revealed data that demonstrates the utility of circulating tumor DNA (ctDNA) methylation markers in the diagnosis, surveillance and prognosis of Hepatocellular Carcinoma. In an AACR (Free AACR Whitepaper) presentation, the company said the findings support that "ctDNA carrying cancer-specific genetic and epigenetic aberrations may enable a non-invasive liquid biopsy for the diagnosis and monitoring of cancer."
PharmaMar – New data presented by PharmaMar at AACR (Free AACR Whitepaper) showed that plitidepsin interacts with and inhibits PKR on the eEF1A2 enzyme. Plitidepsin inhibits this interaction obtaining the induction of cell death, the company announced. PharmaMar said through the bonding to eEF1A2, plitidepsin annuls the oncogenic properties of its target.

On April 17, 2018 NANOBIOTIX (Euronext: NANO – ISIN: FR0011341205), a late clinical-stage nanomedicine company pioneering new approaches to the local treatment of cancer, reported that preclinical data evaluating the activation of the cGAS-STING pathway by NBTXR3 has been presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago, Illinois (April 14-18, 2018) (Press release, Nanobiotix, APR 17, View Source [SID1234525489]).

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NBTXR3 is a first-in-class product designed to destroy, when activated by radiotherapy, tumors and metastasis
through physical cell death and to induce immunogenic cell death leading to specific activation of the immune
system.
Establishing how NBTXR3, activated by radiotherapy, impacts and primes the immune response against tumor
cells is central to Nanobiotix’s immuno-oncology program. Recently, the cGAS-STING pathway has emerged as
the key component of the anti-tumor immune response, along with immunogenic cell death. Therefore,
evaluation of the impact of NBTXR3 on this conserved signaling cascade is essential.

Dr Elsa Borghi, CMO, commented, "cGAS-STING activation is of fundamental importance in establishing an
adaptive anti-tumor immune response. These encouraging preliminary results suggest that NBTXR3 activated by
radiotherapy could increase the activation of this pathway, compared to radiotherapy alone."
"Activation of the cGAS-STING pathway by NBTXR3 nanoparticles exposed to radiotherapy"
J. Marill, N. Mohamed Anesary, A. Darmon, P. Zhang and S. Paris.
Poster number #4571
In this poster, Nanobiotix presents data showing a dose-dependent increase in cGAS-STING pathway activation
with NBTXR3 activated by radiotherapy through both in vitro and in vivo analyses.
In vitro analyses show a significant increase in luciferase activity (reflecting the transcriptional activity of IRF) was
observed in HCT116-DUAL cells treated with NBTXR3 plus RT, compared to radiotherapy alone. Further,
NBTXR3 activated by radiotherapy triggers an increased generation of micronuclei (involved cGAS-STING
response) compared to radiotherapy alone.
In vivo, NBTXR3 activated by radiotherapy leads to a greater production of IFN-b and overexpression of its gene,
compared to radiotherapy alone.
Previous work has demonstrated that NBTXR3 activated by radiotherapy increased cancer cell killing efficiency
along with Immunogenic Cell Death (ICD), compared to radiotherapy alone. Here, in vitro data generated from
HCT116-DUAL and in vivo data from CT26 tumors further demonstrate that NBTXR3 activated by radiotherapy
is able to trigger a stronger activation of the cGAS-STING pathway, compared to radiotherapy alone, even in
combination with the STING agonist 2’,3’-cGAMP. Moreover, NBTXR3 can maximize the effect of 2’,3’-cGAMP,
the natural agonist of STING, when activated by the radiotherapy.
These observations support the rationale for using NBTXR3 with radiation therapy in combination with
immunotherapeutic agents and/or STING agonist to transform tumors into an in-situ cancer vaccine.
These results, obtained in human and mouse colorectal cancer cells models, could have a very positive impact
on the anti-tumoral immune response, potentially transforming non-responding tumors into responding, i.e.
turning them from "cold" to "hot".
NBTXR3 positioning in IO
Many IO combination strategies focus on ‘priming’ the tumor, which is now becoming a prerequisite of turning
a "cold" tumor into a "hot" tumor.
Compared to other modalities that could be used for priming the tumor, NBTXR3 could have a number of
advantages: the physical and universal mode of action that could be used widely across oncology, a one-time
local injection and good fit within existing medical practice already used as a basis for cancer treatment, as well
as a very good chronic safety profile and well-established manufacturing process.
Published preclinical and clinical data indicate that NBTXR3 could play a key role in oncology and could become
a backbone in immuno-oncology.
Nanobiotix’s immuno-oncology combination program opens the door to new developments, potential new
indications, and important value creation opportunities.
***
About American Association for Cancer Research (AACR) (Free AACR Whitepaper) www.aacr.org
The AACR (Free AACR Whitepaper) Annual Meeting is one of the main international oncology events highlighting the best cancer science and medicine
from institutions all over the world. The American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago,
Illinois (April 14-18, 2018).
About NBTXR3
NBTXR3 is a first-in-class product designed to destroy, when activated by radiotherapy, tumors and metastasis through
physical cell death and to immunogenic cell death leading to specific activation of the immune system.
NBTXR3 has a high degree of biocompatibility, requires one single administration before the whole radiotherapy treatment
and has the ability to fit into current worldwide standards of radiation care.
NBTXR3 is being evaluated in head and neck cancer (locally advanced squamous cell carcinoma of the oral cavity or
oropharynx), and the trial targets frail and elderly patients who have advanced cancer with very limited therapeutic options.
The Phase I/II trial has already delivered very promising results regarding the local control of the tumors and a potential
metastatic control through in situ vaccination.
Nanobiotix is running an Immuno-Oncology program with NBTXR3 that includes several studies. In the U.S., the Company
received the FDA’s approval to launch a clinical study of NBTXR3 activated by radiotherapy in combination with anti-PD1
antibodies in lung, and head and neck cancer patients (head and neck squamous cell carcinoma and non-small cell lung
cancer). This trial aims to expand the potential of NBTXR3, including using it to treat recurrent or metastatic disease.
The first market authorization process (CE Marking) is ongoing in Europe in the soft tissue sarcoma indication.
The other ongoing studies are treating patients with liver cancers (hepatocellular carcinoma and liver metastasis), locally
advanced or unresectable rectal cancer in combination with chemotherapy, head and neck cancer in combination with
concurrent chemotherapy, and prostate adenocarcinoma.

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.

On April 17, 2018 Cellectar Biosciences (Nasdaq: CLRB), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of drugs for the treatment of cancer, reported the presentation of a poster entitled "Efficacy of fractionated injections of CLR 131 in an OPM-2 mouse model" at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting underway in Chicago (Press release, Cellectar Biosciences, APR 17, 2018, View Source [SID1234525436]). Jarrod Longcor, chief business officer at Cellectar Biosciences, will conduct the presentation today, from 1:00 pm – 5:00 pm (CT), poster section 43.

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The purpose of the study described in the poster was to evaluate the efficacy of fractionated CLR 131 in an OPM-2 multiple myeloma (MM) mouse model. A statistically significant reduction in tumor volume and an increase in overall survival was observed when mice were given 50uCi of CLR 131 once weekly for 2 weeks compared to all three active comparators in the study; a bortezomib arm dosed 0.6mg/kg twice weekly for two weeks and two single dose cohorts of CLR 131 (50 and 100uCi). The bortezomib dose has been previously shown to be efficacious in this MM model. Additionally, the time it took for tumors to double in size was markedly increased using fractionated dosing in comparison to the other treatments. Moreover, this dosing regimen showed improved tolerability as measured by body weight changes versus a single equivalent bolus dose further supporting the company’s plans to explore fractionated injections of CLR 131 in human clinical trials.

"The results seen in this study are promising because they demonstrate improved outcomes with fractionated injections vs single administration of CLR 131 in an established multiple myeloma animal model," said James Caruso, chief executive officer of Cellectar Biosciences. "We continue to see promise in CLR 131’s ability to demonstrate selective uptake and retention by malignant cells, while minimizing impact on healthy cells."

About CLR 131
CLR 131 is Cellectar’s investigational radioiodinated PDC therapy that exploits the tumor-targeting properties of the company’s proprietary phospholipid ether (PLE) and PLE analogs to selectively deliver radiation to malignant tumor cells, thus minimizing radiation exposure to normal tissues. CLR 131, is in a Phase 2 clinical study in relapsed or refractory (R/R) MM and a range of B-cell malignancies and a Phase 1 clinical study in patients with (R/R) MM exploring fractionated dosing. In 2018 the company plans to initiate a Phase 1 study with CLR 131 in pediatric solid tumors and lymphoma, and a second Phase 1 study in combination with external beam radiation for head and neck cancer.

On April 17, 2018 Deciphera Pharmaceuticals, Inc. (NASDAQ:DCPH), a clinical-stage biopharmaceutical company focused on addressing key mechanisms of tumor drug resistance, reported pre-clinical data for DCC-2618 confirming a broad spectrum of potent inhibition across primary and secondary KIT mutations and primary PDGFRα mutations (Press release, Deciphera Pharmaceuticals, APR 17, 2018, View Source [SID1234525437]). Compared to the FDA approved and investigational compounds tested in this pre-clinical study, DCC-2618 demonstrated the broadest profile of inhibition of primary and secondary KIT mutations and primary PDGFRα mutations. The data will be presented today at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, IL in a poster titled "Inhibition of oncogenic and drug-resistant PDGFRA and KIT alterations by DCC-2618".

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Deciphera is currently evaluating DCC-2618 in multiple clinical studies including INVICTUS, a Phase 3 pivotal study in 4th line and 4th line plus GIST patients, and in a Phase 1 study in other KIT and/or PDGFRα-driven diseases, including 2nd line to 4th line plus GIST, SM, glioblastoma multiforme and other cancers. Deciphera expects to initiate a Phase 3 registration study in 2nd line GIST patients in the second half of 2018 and to report top-line data from the ongoing INVICTUS study in 2019.

"In GIST patients receiving FDA approved therapies, secondary drug resistance KIT mutations frequently result in disease progression. Our pre-clinical results confirm that among the kinase inhibitors tested, both approved and investigational, DCC-2618 exhibits the broadest profile of inhibition against these heterogenous, difficult to treat mutations," said Michael D. Taylor, Ph.D., Deciphera’s President and Chief Executive Officer. "A significant need exists for therapies with the potential to address both activating mutations and other genetic alterations in KIT and PDGFRα, which have been identified in >85% of patients with GIST and >90% of patients with systemic mastocytosis."

These data describe the breadth of inhibition achieved with DCC-2618 and its active metabolite, DP-5439, across both primary and secondary KIT mutations and primary PDGFRα mutations compared to the in vitro profiles of the FDA-approved kinase inhibitors, imatinib, sunitinib, regorafenib, midostaurin and the investigational agent, avapritinib (BLU-285). Highlights from the poster include:

DCC-2618, a Type II switch control kinase inhibitor of KIT and PDGFRα, broadly inhibits KIT mutants in exons 9, 11, 13, 14 17, and 18 and PDGFRα mutants in exons 12, 14, and 18, forcing even aggressively activated kinase mutants into a Type II inactive conformation.

Compared to the approved and investigational compounds tested, DCC-2618 and its active metabolite, DP-5439, exhibit the broadest profile of inhibition across primary and secondary drug-resistant KIT mutations, and primary PDGFRα mutations.

Other Type II inhibitors, such as imatinib, sunitinib and regorafenib, do not broadly inhibit KIT exon-17 mutations or mutations in PDGRFα while Type I inhibitors, such as avapritinib (BLU-285), have weaker activity against KIT mutations in exons 13 and 14.

DCC-2618 also exhibited a superior exon 9 KIT mutation profile compared to imatinib, sunitinib, and avapritinib (BLU-285), including complex KIT mutations involving exon 9 coupled with secondary KIT mutations in exons 13, 14, and 17.

In enzyme assays at relevant cellular levels of adenosine triphosphate (ATP), DCC-2618 broadly inhibited primary and drug-resistant KIT mutants and primary PDGFRα mutants. DCC-2618 also broadly inhibited KIT and PDGFRα mutations in a panel of GIST, mastocytosis, leukemia, lung cancer, and transfected cell assays, as well as in various in vivo xenograft models.

As previously reported, translational liquid biopsy data from the Phase 1 clinical trial has shown that in heavily pre-treated GIST patients, many of whom had received all three of the FDA approved drugs for GIST, DCC-2618 decreased mutant KIT circulating tumor DNA (ctDNA) across the spectrum of KIT exons 9, 11, 13, 14, 17, and 18.

About DCC-2618
DCC-2618 is a KIT and PDGFRα kinase switch control inhibitor in clinical development for the treatment of KIT and/or PDGFRα-driven cancers, including gastrointestinal stromal tumors, systemic mastocytosis and glioblastoma multiforme. DCC-2618 was specifically designed to improve the treatment of GIST patients by inhibiting a broad spectrum of mutations in KIT and PDGFRα. DCC-2618 is a KIT and PDGFRα inhibitor that blocks initiating KIT mutations in exons 9, 11, 13, 14, 17, and 18, involved in GIST as well as the primary D816V exon 17 mutation involved in SM. DCC-2618 also inhibits primary PDGFRα mutations in exons 12, 14,and 18, including the exon 18 D842V mutation, involved in a subset of GIST.