1stOncology™: Cancer Intelligence Service – Page 14390 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Brooklyn ImmunoTherapeutics Announces Presentation of Positive Results of IRX-2 Therapy in Resectable Breast Cancer and Head and Neck Cancer at the 33rd Annual Meeting of the Society for Immunotherapy of Cancer

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

Celldex Presents Emerging MerTK Antibody Program at the Society for Immunotherapy of Cancer’s 33rd Annual Meeting

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.

"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.

CRISPR Therapeutics and MaxCyte Expand Clinical and Commercial License Agreement into Oncology

On November 9, 2019 CRISPR Therapeutics (NASDAQ:CRSP) and MaxCyte reported the expansion of their existing relationship by entering into a non-exclusive commercial license agreement that will allow CRISPR Therapeutics to deploy MaxCyte’s Flow Electroporation Technology to develop CRISPR/Cas9-based therapies in immuno-oncology (Press release, MaxCyte, NOV 9, 2018, View Source [SID1234537624]).

"As we advance our allogeneic CAR-T programs into the clinic, we are preparing for the future by securing our access to the leading ex vivo delivery platform for both clinical and commercial use, just as we previously did for our hemoglobinopathy developmental candidates," said Samarth Kulkarni, CEO of CRISPR Therapeutics.

The expanded relationship builds on an existing agreement announced in March 2017 which allowed for the development of commercial therapeutics for hemoglobin-related diseases. Under the terms of the new license agreement, CRISPR Therapeutics will obtain non-exclusive development and commercial-use rights to MaxCyte’s cell engineering platform to develop immuno-oncology cell therapies. MaxCyte will supply its technology to CRISPR Therapeutics as part of the enabling technology license agreement and will receive milestone and sales-based payments in addition to other licensing fees.

"The expansion of our relationship with CRISPR Therapeutics signifies a key milestone for MaxCyte and our technology, providing further validation for the value and versatility of our technology as a leading enabler of next-generation cell-based therapies," said Doug Doerfler, President & CEO of MaxCyte, Inc. "CRISPR Therapeutics is a leader in gene editing, and we are very pleased to expand our collaboration into new therapeutic areas as we continue to explore the use of our technology to advance medicines to market that will make a difference for patients."

MaxCyte’s Flow Electroporation Technology enables the engineering of a broad range of therapeutically-relevant cell types at high efficiency while maintaining high viability and recovery. CRISPR Therapeutics’ immuno-oncology cell therapy programs rely on ex vivo gene editing, where the CRISPR components are delivered into T-cells using the MaxCyte technology.

SITC 2018: further analyses of the Phase II study of the combination of monalizumab and cetuximab in head and neck patients show encouraging survival data in both subgroups of IO-naïve and IO-pretreated SCCHN patients

On November 12, 2018 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH), reported exploratory subgroup analyses and preliminary translational data from the Phase II trial evaluating the combination of monalizumab and cetuximab (anti-EGFR) in previously treated patients with recurrent and/or metastatic squamous cell carcinoma of the head & neck (R/M SCCHN) (Press release, Innate Pharma, NOV 9, 2018, View Source [SID1234531226]). Monalizumab is a first-in-class checkpoint inhibitor targeting NKG2A inhibitory receptors expressed on tumor-infiltrating cytotoxic CD8 T lymphocytes and NK cells.

"The subgroup analysis revealed very interesting durable responses in both IO-naïve and IO-pretreated patients," commented Pierre Dodion, Chief Medical Officer of Innate Pharma. "Patients who have failed on IO-therapy currently have no other treatment option. The fact that they appear to benefit with prolonged survival is rather remarkable and prompted us to advance our clinical program. Discussions are taking place in parallel with regards to the next steps in IO naïve patients".

"The high disease control rate that we observed in this study along with the favorable trends in progression-free and overall survival, including a preliminary estimate of median overall survival of 10.3 months, are very encouraging," commented Professor Roger B. Cohen, Principal Investigator of the study. "We also saw evidence of clinical activity in both IO-naive and IO-pretreated patients. If confirmed, these data would provide support for a highly novel immunotherapeutic combination with a unique mechanism of action for the treatment of patients with head & neck cancer."

Data from the cohort of 40 patients were reported at 2018 ESMO (Free ESMO Whitepaper) congress in October. Exploratory subgroup analysis revealed encouraging responses, durability of response, PFS and OS in IO-naïve and IO-pretreated patients.

Cut-off August 31, 2018

All patients

(n=40)

IO-naïve

(n=23)

IO-pretreated

(n=17)

ORR [95% CI]

27.5% [16-43]

35% [19-55]

18% [6-41]

Median PFS [95% CI]

5.0 m [3.7-6.9]

4.0 m[3.7-10.6]

5.0 m [3.5-NR]

Median OS [95% CI]

10.3 m [7.3-NR]

10.3 m [7.2-NR]

12.8 m [6.0-NR]

DCR 24 weeks

35% [22-51]

39% [22-59]

29% [13-53]

Median time to response [range]

1.6 m [1.5-3.9]

1.7 m [1.5-3.9]

1.6 m [1.6-3.1]

Median duration of response [95% CI]

5.6 m [3.8-NR]

5.3 m [3.8-NR]

5.6 m [3.7-NR]

Eric Vivier, Chief Scientific Officer of Innate Pharma, said: "We are combining the use of state-of-the-art technologies including high-dimensional flow cytometry, single cell RNA seq and computational pathology, to monitor the immune response in patients. Data support the mode of action of monalizumab as unleashing a multilayered immune response involving both NK and T cells. As such, monalizumab appears as a first-in-class second generation immune checkpoint inhibitor with a large spectrum of immune targets. He added: "While preliminary, translational results suggest that the combination of monalizumab and cetuximab is associated with a reshaping of "cold tumors" into "hot tumors" prone to sustain tumor immunity".

Preliminary biomarker analysis show indeed that while the combination did not impair the distribution or absolute counts of peripheral NKG2A+ NK and CD8+ T cells, an infiltration of NK cells and CD8+T cells is detected very early upon treatment (day 15) at the tumor bed. Further, tumor-infiltrating NK and CD8+ T cells may be predictive of RECIST response, tumor reduction and PFS.

Importantly, the activity of the monalizumab and cetuximab combination appears to occur across HPV status, tumor burden and PD-L1 expression.

OncoMed Announces Early Clinical Data for anti-TIGIT Antibody

On November 9, 2018 OncoMed Pharmaceuticals, Inc. (NASDAQ: OMED), a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer therapeutics, reported initial results from the Phase 1a dose escalation portion of a Phase 1a/b trial of etigilimab, the company’s anti-TIGIT antibody (Press release, OncoMed, NOV 9, 2018, View Source [SID1234531219]). TIGIT (T-cell immunoreceptor with Ig and ITIM domains) is a next generation checkpoint receptor shown to block T-cell activation and the body’s natural anti-cancer immune response. OncoMed’s anti-TIGIT checkpoint inhibitor candidate is an IgG1 monoclonal antibody which binds to the human TIGIT receptor on T-cells with a goal of improving the activation and effectiveness of T-cell and NK cell tumor-killing activity. The data were presented today at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) meeting taking place in Washington, D.C.

The initial results from the Phase 1a dose escalation portion of the Phase 1a/b trial included data from 18 patients with a variety of late stage metastatic cancers including colorectal, endometrial, pancreatic, among others, who were treated with etigilimab at doses ranging from 0.3 to 20 mg/kg every other week. There were no dose-limiting toxicities through the 20 mg/kg every other week dose. In this "all comers" difficult-to-treat patient population, stable disease was observed in 7 (38.9%) patients with prolonged disease control seen in some patients with the longest durations of stable disease being 205 and 225 days. Of the remaining 11 patients in the study, ten patients had progressive disease, and one patient did not meet criteria to be evaluated for efficacy. The most frequent treatment-related adverse events were rash (27.8%), fatigue (16.7%), nausea (16.7%), pruritus (16.7%), and cough (11.1%). Immune-related adverse events, signaling immune activation included rash (27.8%), pruritus (16.7%), autoimmune hepatitis (5.6%) and stomatitis (5.6%). Grade 3 or higher treatment-related AEs included rash (16.7%), and abdominal pain, embolism, hypertension, and pulmonary embolism (11.1% each).

Biomarker analysis demonstrated a significant reduction of peripheral T regulatory cells (Tregs), most significant at doses ≥ 10 mg/kg, and signals of immune activation. These results are consistent with preclinical studies with a surrogate anti-TIGIT antibody and suggest select immune cell depletion and activation of T cell signaling in patients treated with the drug.

"These data indicate that etigilimab was well-tolerated by patients and showed modulation of specific subsets of peripheral T cells," said John Lewicki, Ph.D., President and Chief Executive Officer of OncoMed. "The decrease in peripheral Tregs and observations of stable disease in certain patients are consistent with the expected mechanisms of our IgG1 anti-TIGIT antibody."

The company is currently enrolling a single agent Phase 1a expansion cohort in select tumor types. Concurrently, the company is also enrolling the phase 1b portion of the trial where escalating doses of etigilimab are given in combination with nivolumab in the treatment of patients with solid tumors who have progressed after treatment with anti-PD1 or anti-PD-L1. The trial will define a dosing regimen that could provide the basis for expanded studies of etigilimab in combination with anti-PD1.

About TIGIT
TIGIT and its ligands, PVR and PVR-L2 comprise a novel immune checkpoint which blocks T-cells from attacking tumor cells and is similar in structure and function to the inhibitory protein PD-1. OncoMed’s anti-TIGIT antibody (etigilimab) is intended to activate the immune system through multiple mechanisms and to enable anti-tumor activity. At the 2018 AACR (Free AACR Whitepaper) Annual Meeting, OncoMed presented preclinical data (Abstract 5627) which demonstrated that anti-TIGIT treatment reduced the abundance of Tregs within tumors in animal models. Mechanistic studies demonstrated an important contribution of effector function for anti-tumor efficacy. Using a surrogate anti-TIGIT antibody, potent single-agent dose-dependent anti-tumor efficacy was demonstrated on large established CT26 WT tumors and in other models. Anti-TIGIT efficacy was shown to require effector function for tumor growth inhibition and biomarker analysis demonstrated reduction of Treg frequency and activation of T-cells and NK cells as part of the mechanism of action of anti-TIGIT. Additionally in a human tissue study, TIGIT expression on Tregs was found to be considerably higher than on CD8+ T-cells in multiplexed IHC panels across a panel of multiple solid tumors types. This program is part of OncoMed’s collaboration with Celgene.