On November 11, 2018 Generon Corporation, a leading biopharmaceutical company in China, reported it received approval for the Company’s Investigational New Drug (IND) application from the State Food and Drug Administration (SFDA) of the People’s Republic of China to initiate a Phase I clinical trial for A-319 in patients with B cell malignancies (Press release, Generon (Shanghai), NOV 11, 2018, View Source [SID1234531111]). A-319 is Generon’s second bispecific antibody in clinical development.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

A-319 is the first CD19 engaging bispecific antibody approved by the SFDA for clinical trials in China. The CD3/CD19 bispecific antibody was developed using Generon’s Immuno-Therapy Antibody (ITab)TM technology platform. The IND approval enables Generon to commence Phase I clinical trials in China enrolling patients with B cell malignancies including acute lymphoblastic leukemia (ALL) and B cell lymphoma.

Dr. Mi Jian Qing, Professor at Ruijin Hospital, Shanghai Jiaotong University expressed his enthusiasm about the biology of A-319 and the potential benefits for ALL patients. He commented: "Obtaining the SFDA’s approval for the A-319 Phase I trial is a significant accomplishment for Generon’s ITabTM platform. The IND approval is another step in demonstrating Generon’s innovative capabilities".

Yifan Pharmaceuticals, Generon’s parent company, congratulated Generon’s team on the continued effort to develop innovative therapies. Dr. Xiao Qiang Yan, CEO and CSO of Generon, said, "Initiation of a Phase I study for A-319 in China is one of Generon’s goals this year. A-319 has a similar mechanism of action to eliminate malignant B cells to those of CAR-T and other CD19/CD3 bispecific antibodies, but it is more convenient for patient dosing and potentially with better safety. A-319 is our second T-cell activating bispecific antibody to enter clinical development. Generon is expanding its ITabTM pipeline for both liquid and solid tumors and committed to bringing innovative immune-oncology antibodies to cancer patients in China and the world".

B cell malignancies

B cell malignancies refer to the different types of cancers that form in B cells in the immune system, including B-cell lymphomas and B-cell leukemia. B-cell lymphoma may be either indolent (slow-growing) or aggressive (fast-growing). Most B-cell lymphomas are non-Hodgkin lymphomas (NHL). There are many different types of B-cell non-Hodgkin lymphomas including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). B-cell leukemia includes B-cell chronic lymphocytic leukemia (CLL), Acute lymphoblastic leukemia (ALL), B-cell prolymphocytic leukemia (PLL), and hairy cell leukemia (HCL). The prognosis and treatment of B cell malignancies depend on the specific type of the B cell lymphoma/leukemia, as well as the stage and grade. Recent immunotherapy (T-cell activating) approaches have demonstrated significant clinical benefits for patients.

About A-319

A-319 is a T-cell activating bispecific antibody (BsAb) designed to target CD19 and CD3 (anti-CD19, anti-CD3) and is under development for the treatment of patients with B cell malignancies including B-cell leukemia and B-cell lymphoma. A-319 activates T lymphocytes in a patient to kill CD19 expressing malignant B-cells.

On November 10, 2018 Jounce Therapeutics, Inc. (NASDAQ: JNCE), a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, reported that reverse translational and biomarker data derived from its ICONIC (ICOS AgONist Antibody for Immunotherapy in Cancer Patients) trial of JTX-2011 and preclinical data from the ICOS (Inducible T cell CO-Stimulator) program were presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 33rd Annual Meeting, being held November 9-11, 2018 in Washington, D.C (Press release, Jounce Therapeutics, NOV 10, 2018, View Source;p=RssLanding&cat=news&id=2376614 [SID1234531232]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The data presented at SITC (Free SITC Whitepaper)’s 33rd Annual Meeting demonstrate the role of JTX-2011 in the emergence and agonism of ICOS hi CD4 T effector cells and provide further evidence in support of the biological and clinical activity of JTX-2011. The regimens we are advancing, including ongoing combinations with ipilimumab, are grounded in these important scientific findings," said Elizabeth Trehu, M.D., chief medical officer of Jounce Therapeutics. "New insights from our Translational Science Platform continue to inform JTX-2011 clinical development. We believe our science-based approach is necessary to develop new immunotherapies to benefit cancer patients."

Data presented from ICONIC patients demonstrate the agonistic properties of JTX-2011. These data are in addition to the subset analysis data presented at ASCO (Free ASCO Whitepaper) 2018 demonstrating the emergence of ICOS hi CD4 T cells in the bloodstream in all patients with ≥30% target lesion tumor reductions, both in patients treated with JTX-2011 monotherapy and in combination with nivolumab. The ICOS hi CD4 T cells were not observed in patients with primary progressive disease.

"Through additional reverse translational studies presented today, we established two key insights that provide the scientific foundation for the next stage of development of JTX-2011," said Richard Murray, Ph.D., chief executive officer and president of Jounce Therapeutics. "First, the emergence of these ICOS hi CD4 T cells was related to JTX-2011, as it has not been detected in a separate study we conducted of responding and non-responding patients that received PD-1/L1 inhibitor monotherapy treatment; and second, in vitro experimental data showed that JTX-2011 only activates CD4 T cells if they already express high levels of ICOS. Additionally, new preclinical tumor model data presented in a separate poster, strengthens our belief that agents that induce ICOS hi CD4 T cells detectable in the bloodstream, such as anti-CTLA-4, may be attractive combination partners for JTX-2011."

In a poster titled "Emergence of an ICOS hi CD4 T cell subset correlates with tumor reductions in subjects treated with the ICOS agonist antibody JTX-2011," Jounce researchers describe the reverse translational efforts ongoing in the ICONIC trial including:

Follow-up on the initial observation of the emergence of ICOS hi CD4 T cells. Emergence of this cell population, which correlated with clinical benefit in patients treated with both JTX-2011 monotherapy and in combination with nivolumab, was presented at ASCO (Free ASCO Whitepaper) in June 2018. These data build upon the initial observation and provides further characterization of the emerging cell population as T effector and not T regulatory cells and includes evidence that the cells do not emerge in patients responding to PD-1 monotherapy.
Additional in vitro data presented demonstrate that JTX-2011 alone induces a cytokine response from CD4 T cells, only if the T cells have pre-existing ICOS hi characteristics.
CTLA-4 inhibition has been shown to induce a population of ICOS hi cells in the bloodstream, while PD-1 inhibitors do not, and these observations further support the biological rationale for the ongoing clinical development of JTX-2011 in combination with ipilimumab.
In a poster titled "Inducible T cell Co-stimulator (ICOS) is upregulated on lymphocytes following radiation of tumors and ICOS agonism in combination with radiation results in enhanced tumor control," Jounce collaborators at the Earle A. Chile’s Research Institute, Providence Portland Medical Center, highlight the benefit of upregulation of ICOS in circulating and intra-tumoral T cells by radiation and its role in effective combination treatment with an ICOS agonist antibody to mediate tumor reduction. The data presented demonstrate:

The combination of radiation therapy and treatment with an ICOS agonist antibody led to increased anti-tumor response in an immunogenic mouse tumor model.
In a less immunogenic tumor model, response required the combination of ICOS agonist and PD-1 antagonist with radiation, suggesting again that ICOS agonism in combination with modalities that upregulate ICOS, such as with radiation, may represent an attractive regimen for combination immunotherapy of anti-PD-1 resistant tumors.
Both posters are available on the Investors and Media section of the Jounce Therapeutics website under "Presentations & Publications" at www.jouncetx.com.

About JTX-2011
Jounce’s lead product candidate, JTX-2011, is a monoclonal antibody that binds to and activates ICOS, a protein on the surface of certain T cells. Preclinical data support that JTX-2011 may have a dual mechanism of action that stimulates anti-tumor T effector cells, and also reduces the immunosuppressive T regulatory cells in the tumor microenvironment. The company is developing JTX-2011 to treat solid tumors as a single agent and in combination with other therapies.

On November 10, 2018 Brooklyn ImmunoTherapeutics, a biopharmaceutical company focused on exploring the role that cytokine-based therapy can have in treating patients with cancer, and Providence Cancer Institute reported the clinical results of IRX-2 therapy in resectable breast cancer and head and neck cancer that were presented in an oral presentation at the 2018 Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) on November 10th at the Walter E. Washington Convention Center in Washington, D.C (Press release, Brooklyn ImmunoTherapeutics, NOV 10, 2018, View Source [SID1234531112]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

IRX-2 is an allogeneic, cell-derived biologic with multiple active cytokine components, including IL-2, that act on various parts of the immune system to activate the entire tumor microenvironment.

"The clinical results presented today demonstrate that treatment with IRX-2 was associated with a mean 116% increase in tumor-infiltrating lymphocytes in patients with early stage breast cancer and a mean increase of 58% in head and neck squamous cell carcinoma," said David B. Page, M.D., Earle A. Chiles Research Institute, a division of Providence Cancer Institute in Portland, Oregon, and the presenter at SITC (Free SITC Whitepaper)’s 33rd Annual Meeting. "Moreover, IRX-2 therapy was also associated with an increase in PD-L1 RNA upregulation in the early stage breast cancer patients and was well-tolerated in both the breast cancer and head and neck cancer patients enrolled in these clinical trials. Together these results support the further evaluation of IRX-2 with anti-PD-1 and neoadjuvant chemotherapy in stage II-III triple negative breast cancer as well as ongoing follow-up of a randomized Phase 2 INSPIRE trial in head and neck cancer."

"These highly encouraging clinical results support further study of IRX-2 as a potential important new immunotherapeutic drug candidate for the treatment of both breast cancer and head and neck cancer," said Mark Leuchtenberger, interim President and CEO of Brooklyn ImmunoTherapeutics. "We believe that IRX-2, both as a single agent and in combination with other anti-cancer agents, can potentially improve patient outcomes in these difficult-to-treat indications as well as in the treatment of other cancers. On-going studies, including the Phase 2B INSPIRE trial and an investigator-sponsored trial in squamous cervical intraepithelial neoplasia 3 or vulvar intraepithelial neoplasia 3, are further exploring the potential of IRX-2 in treating cancer."

Results

In the early stage breast cancer trial (ESBC), 16 patients were enrolled and evaluable for tumor-infiltrating lymphocyte (TIL) analysis, and the head and neck squamous cell carcinoma (HNSCC) trial is fully enrolled at 105 patients with 36 patients evaluable at the time of analysis. In both trials, all patients received all planned injections with no treatment-related surgical delays, complications, or treatment-related grade III/IV toxicities. Treatment was associated with a mean 116% relative increase in TILs (range –36% to +1275%, p = 0.02) in ESBC and a mean 58% relative increase (range –57 to +452%, p=0.01) in HNSCC. Treatment was associated with PD-L1 RNA upregulation in EBSC (mean +54%, range –53% to +185%, p=0.04). RNA analysis in ESBC and HNSCC revealed concordant increases in cytokine gene expression, including CXCL2, CCL4, CXCR4, and CXCL12 as well as transcription factors including FOS, ETS1, NFκB, EGR1/2 which are involved in T-cell activation and differentiation. Augmentation of ITGAE (CD103), a known marker of memory T-cell activation in EBSC cohort was also observed

On November 10, 2018 Dendrogenix a company developing a innovative therapies, reported a first funding round of €3.6M, including €1.2M in capital and €2.4M in grants and recoverable advances from walloon region (Press release, Dendrogenix, NOV 10, 2018, View Source [SID1234539438]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

On November 10, 2018 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported data from the Company’s MerTK antibody program in a poster session at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 33rd Annual Meeting(Press release, Celldex Therapeutics, NOV 10, 2018, View Source [SID1234531099]). MerTK is emerging as a promising target for cancer immunotherapy. Its expression in innate immune cells is believed to negatively regulate immune responses and genetic removal of MerTK renders mice resistant to some tumors.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"MerTK has been described as an immune checkpoint in macrophages, dendritic cells and other immune cells," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "Through our significant discovery effort, we have identified two unique antibodies that modulate this pathway resulting in profound levels of cytokine and chemokine production, and importantly we have developed preclinical models that support the premise that antibody modulation of MerTK can lead to antitumor responses."

As detailed in the presentation, Celldex developed a large panel of antibodies to MerTK and investigated their ability to enhance activation of innate immune cells. Two lead candidate human anti-MerTK antibodies were then selected based on their potent induction of cytokines from human macrophages, dendritic cells, and monocytes. Treatment of dendritic cells with the MerTK antibodies led to production of a broad array of pro-inflammatory cytokines and chemokines. Isolated peripheral blood monocytes were found to express high levels of MerTK and were similarly activated by the MerTK antibodies.

Emerging proof of concept data was established in preclinical models. Using a surrogate anti-mouse MerTK​ antibody, similar increases in the levels of cytokines were observed in the blood of mice shortly after treatment with the antibody. The anti-mouse MerTK​ antibody led to increased survival when dosed alone or in combination with a PD-1 inhibitor in a colon cancer model. To test the lead clinical candidates, which bind to human and not mouse MerTK, Celldex generated human MerTK transgenic mice that were shown to appropriately express and regulate human MerTK on macrophages. This will now allow testing of the anti-human MerTK mAbs in inflammation and tumor models. Collectively, the data support that anti-MerTK mAbs can modulate MerTK activity consistent with its role as a negative immune regulator and provide an exciting new approach to enhance innate immune function in cancer.

Celldex is currently completing the preclinical studies for selection of the lead candidate to advance into development activities. These studies include investigating the antitumor effect of combinations with Celldex’s immunotherapy product candidates.