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Corvus Pharmaceuticals Announces Results of Preclinical Studies Demonstrating Enhanced Immune Responses and Anti-Tumor Activity with CPI-444, an Investigational Immuno-Oncology Therapy

On April 19, 2016 Corvus Pharmaceuticals, Inc. (NASDAQ:CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of novel immuno-oncology therapies, reported results of three preclinical studies of CPI-444, the Company’s lead oral checkpoint inhibitor (Press release, Corvus Pharmaceuticals, APR 19, 2016, View Source;p=irol-newsArticle&ID=2158492 [SID:1234512141]). The studies demonstrated that CPI-444, a selective and potent inhibitor of the adenosine A2A receptor, was effective in stimulating various immune cells, generating anti-tumor immunity, suppressing tumor growth and delaying tumor progression in animal models of cancer. The data were presented in oral and poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans.

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"These preclinical studies demonstrate that CPI-444 enhances the immune response to various tumors in animal models of melanoma, breast and colon cancer. Enhancement of T-cell function was also corroborated with adoptively transferred T-cells and with tumor vaccines, indicating that this agent may have broad applications in immuno-oncology," said Richard A. Miller, M.D., an oncologist and co-founder, president and chief executive officer of Corvus. "These studies support our commitment to advancing the clinical development of CPI-444 as an immuno-oncology therapy for many types of cancer. Based on these study findings and others, we have begun enrolling patients in a Phase 1/1b clinical trial to evaluate the safety, tolerability and preliminary efficacy of CPI-444 as a single agent and in combination with an anti-PD-L1 in patients with solid tumors."

The Adenosine A2A Receptor Antagonist, CPI-444, Blocks Adenosine-Mediated T-Cell Suppression and Exhibits Anti-Tumor Activity Alone and in Combination with Anti-PD-1 and Anti-PD-L1 (abstract #2337)
Data from this preclinical study were presented in a poster session by Stephen Willingham, Ph.D., senior scientist at Corvus Pharmaceuticals. Results showed that CPI-444 restored T-cell activation in vitro in T-cells that were treated with immuno-suppressive levels of adenosine. CPI-444 demonstrated single-agent anti-tumor activity and synergized with either anti-PD-1 or anti-PD-L1 in multiple animal tumor models, resulting in a significant number of cured animals. CPI-444 combined with anti-PD-L1 treatment resulted in increased CD8+ T-cell infiltrates in tumors, indicating a heightened anti-tumor immune response. In tumor-bearing mice cured by treatment with CPI-444, long-term anti-tumor immunity was demonstrated by showing that all these mice were protected from tumor re-challenge.

Inhibition of Adenosine A2A Receptor (A2AR) by CPI-444 Enhances CD8+ T-Cell Killing of a HER-2/neu Expressing Murine Tumor (abstract #320)
Data from this preclinical study were presented by Blake Scott, a member of the lab of Elizabeth Jaffee, M.D., in The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine. Jaffee also is associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins. Results showed that CPI-444 enhanced the activity of adoptively transferred, cancer-specific CD8+ T-cells when administered with a T-cell-inducing tumor vaccine.

Adenosine A2A Receptor (A2AR) Antagonist as a Means of Enhancing the Efficacy of Checkpoint Blockade and Adoptive T-Cell Therapy (abstract #4364)
Data from this preclinical study were presented in an oral session by Robert D. Leone, M.D., Ph.D., of The Sidney Kimmel Comprehensive Cancer Research Center at Johns Hopkins University School of Medicine. Treatment of animals with CPI-444 enhanced tumor immunity by lowering the expression of other inhibitory checkpoint receptors on tumor infiltrating immune cells (e.g., Lag 3, Tim 3 and PD-1). CPI-444 also enhanced the efficacy of adoptively transferred T-cells, leading to suppressed tumor growth and increased survival compared with controls. CPI-444 increased the expansion of antigen-specific T-cells in vitro and synergized with anti-PD-1 antibody treatment and glutamine metabolism inhibitors in animal models of colon tumors. A co-author of the study is Jonathan Powell, M.D., Ph.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center and associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.

ABOUT ADENOSINE A2A RECEPTOR ANTAGONISTS
Over the last several years, significant progress has been made in developing immunotherapies for the treatment of cancer, in part due to the development of checkpoint inhibitors — antibodies that block immuno-suppressive mechanisms.

Tumors evade immune attack by usurping pathways that negatively regulate immune responses. Adenosine in the tumor microenvironment leads to the activation of the A2A receptor and has been shown to represent one such negative immune regulatory mechanism. Because the tumor microenvironment produces relatively high concentrations of adenosine, blocking A2A receptor activation has the potential to enhance anti-tumor immunity. Data have demonstrated the ability of A2A receptor blockade to enhance anti-tumor immunity, checkpoint blockade and adoptive T-cell therapy. Studies to date support the development of A2A receptor antagonists as novel immunotherapy treatments.

ABOUT CPI-444
CPI-444, Corvus’s lead checkpoint inhibitor, is an adenosine A2A receptor antagonist. It is designed to disable a tumor’s ability to subvert attack by the immune system by inhibiting adenosine in the tumor microenvironment. CPI-444 is a small molecule that is taken orally. It is in development as an immuno-oncology therapy for the treatment of patients with solid tumors.

Corvus is currently evaluating CPI-444 in a multicenter Phase 1/1b clinical trial in patients with various solid tumors. This successive expansion cohort trial is examining the activity of CPI-444 both as a single agent and in combination with atezolizumab (MPDL3280A), Genentech’s investigational cancer immunotherapy. Atezolizumab is a fully humanized monoclonal antibody targeting protein programmed cell death ligand 1 (PDL-1). Corvus is conducting the trial with Genentech, a member of the Roche Group, under a clinical trial collaboration the two companies entered into in October 2015.

Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells.

The molecular mechanism responsible that determines cell fate after mitotic slippage is unclear. Here we investigate the post-mitotic effects of different mitotic aberrations–misaligned chromosomes produced by CENP-E inhibition and monopolar spindles resulting from Eg5 inhibition. Eg5 inhibition in cells with an impaired spindle assembly checkpoint (SAC) induces polyploidy through cytokinesis failure without a strong anti-proliferative effect. In contrast, CENP-E inhibition causes p53-mediated post-mitotic apoptosis triggered by chromosome missegregation. Pharmacological studies reveal that aneuploidy caused by the CENP-E inhibitor, Compound-A, in SAC-attenuated cells causes substantial proteotoxic stress and DNA damage. Polyploidy caused by the Eg5 inhibitor does not produce this effect. Furthermore, p53-mediated post-mitotic apoptosis is accompanied by aneuploidy-associated DNA damage response and unfolded protein response activation. Because Compound-A causes p53 accumulation and antitumour activity in an SAC-impaired xenograft model, CENP-E inhibitors could be potential anticancer drugs effective against SAC-impaired tumours.

Approaches to Interchain Cysteine-Linked ADC Characterization by Mass Spectrometry.

Therapeutic antibody-drug conjugates (ADCs) harness the cell-killing potential of cytotoxic agents and the tumor targeting specificity of monoclonal antibodies to selectively kill tumor cells. Recent years have witnessed the development of several promising modalities that follow the same basic principles of ADC based therapies but which employ unique cytotoxic agents and conjugation strategies in order to realize therapeutic benefit. The complexity and heterogeneity of ADCs present a challenge to some of the conventional analytical methods that industry has relied upon for biologics characterization. This current review will highlight some of the more recent methodological approaches in mass spectrometry that have bridged the gap that is created when conventional analytical techniques provide an incomplete picture of ADC product quality. Specifically, we will discuss mass spectrometric approaches that preserve and/or capture information about the native structure of ADCs and provide unique insights into the higher order structure (HOS) of these therapeutic molecules.

Otsuka’s U.S. Subsidiary Astex Pharmaceuticals Enters Clinical Trial Collaboration to Explore the Potential of Combining Guadecitabine (SGI-110) with Atezolizumab in the Treatment of Acute Myeloid Leukemia

On April 19, 2016 Astex Pharmaceuticals, Inc., a pharmaceutical company dedicated to the development of novel small molecule oncology therapeutics, reported that it has entered into a clinical collaboration with Genentech (Press release, Otsuka, APR 19, 2016, View Source;date=2016-04-20 [SID:1234511123]).

The collaboration will evaluate the potential for combining Astex’s next-generation hypomethylating agent, guadecitabine (SGI-110), with Genentech’s investigational anti-PD-L1 monoclonal antibody, atezolizumab, in the treatment of acute myeloid leukemia (AML). An initial Phase 1b study will investigate the safety and pharmacology of the combination.

OncoSec Presents Positive Melanoma Clinical Data at American Association for Cancer Research (AACR) Annual Meeting 2016

On April 19, 2016 OncoSec Medical Incorporated ("OncoSec") (NASDAQ: ONCS), a company developing DNA-based intratumoral cancer immunotherapies, today presented long-term, follow-up data of patients who were treated with its investigational therapy ImmunoPulse IL-12 and later went on to receive an anti-PD-1/PD-L1 therapy (Press release, OncoSec Medical, APR 19, 2016, View Source [SID:1234511122]). These data suggest that ImmunoPulse IL-12 may prime and enhance response rates to PD-1/PD-L1 blockade. Alain Algazi, MD, skin cancer specialist in the Melanoma Center at the UCSF Helen Diller Family Comprehensive Cancer Center, presented the findings in an oral presentation entitled "Intratumoral electroporation of plasmid IL-12 can prime response to anti-PD1/PD-L1 blockade in patients with Stage III/IV-M1a melanoma" (Abstract #CT134) at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA.

"We are encouraged by the data from this analysis, which show that intratumoral IL-12 DNA with electroporation can prime the immune system and help improve patient response to anti-PD-1," said Dr. Algazi. "These results are being validated prospectively in a Phase II clinical trial and they could make a clinically meaningful impact on patient outcomes and address a great unmet need in immuno-oncology."

These new data were generated from a single-site retrospective analysis of the Company’s Phase II monotherapy clinical study of ImmunoPulse IL-12, which employs intratumoral electroporation to enhance delivery of DNA-based interleukin-12 (IL-12), in patients with advanced melanoma. After completing treatment with ImmunoPulse IL-12, a subset of patients subsequently received an anti-PD-1/PD-L1 therapy either as their next line of treatment or a later line of treatment. Patients with documented follow-up history and evaluable for anti-PD-1/PD-L1 response were included in this analysis.

In this study, 34 patients were enrolled and treated with ImmunoPulse IL-12 alone. Fourteen of these 34 patients went on to receive a systemic anti-PD-1/PD-L1 therapy and were evaluable for PD-1/PD-L1 overall response rate ("ORR") using immune-related response criteria. The PD-1/PD-L1-associated ORR among patients was 64% (9/14). The analysis showed 36% of patients (5/14) had a complete response (CR), 29% of patients (4/14) had a partial response (PR), 14% percent of patients (2/14) experienced stable disease, and 21% of patients (3/14) had progressive disease. Furthermore, 8 of these 14 evaluable patients received a systemic anti-PD-1/PD-L1 antibody with no intervening therapy after treatment with ImmunoPulse IL-12. Of these 8 patients, an ORR of 75% was observed (50% CR and 25% PR).

Additionally, multiple biomarker analyses demonstrate that ImmunoPulse IL-12 therapy promotes the generation of activated natural killer and functional T cell immune subsets in the periphery as well as CD8+ tumor infiltrating lymphocytes (TIL), which may help trigger the PD-1 immune checkpoint (i.e. "adaptive immune resistance") to provide the "substrate" for effective anti-PD-1/PD-L1 therapy.

"Although one always needs to be cautious regarding the interpretation of retrospective analyses, these data are consistent with our hypothesis that ImmunoPulse IL-12 is driving a specific anti-tumor TIL response, which primes the patient for an enhanced response to PD-1 blockade," said Robert H. Pierce, MD, Chief Scientific Officer. "We look forward to following up on these observations with interim data from our ongoing combination trial in patients with melanoma investigating ImmunoPulse IL-12 and the anti-PD-1 therapy, pembrolizumab, later this year."

The full-text abstract is available and can be viewed on AACR (Free AACR Whitepaper)’s website at www.aacr.org. The presentation is available in the Publications section of OncoSec’s website.

About Melanoma
Melanoma is one of the most dangerous forms of skin cancer and accounts for the vast majority of skin cancer deaths.1 When melanoma is caught early enough, surgical excision can be curative in the majority of Stage I and II melanomas. The overall 5-year survival rate for patients with localized melanoma is 98% in the United States.1 At later stages, malignant melanoma remains a deadly and frequently difficult to treat cancer. The overall 5-year survival rate for patients falls to 17% when the disease metastasizes to distant sites or organs.1 Approximately 8,780 patients are diagnosed with Stage III and IV melanoma in the United States each year.2

Melanoma that has spread to distant sites may be treated with surgery, immunotherapy, chemotherapy and/or radiation therapy.1 Numerous chemotherapy regimens have been tested in melanoma with only modest success and limited overall survival benefit.3 Immunotherapies, such as checkpoint inhibitors, have demonstrated improvement in overall survival of patients compared to chemotherapy.3

While immunotherapy can be extremely effective, the majority of patients will not respond to anti-PD-1 therapy alone, representing a great unmet need in oncology. However, researchers are focusing efforts on targeting pathways of T cell activation.4 The presence of CD8+ T cells seems to correlate with improved prognosis and long-term survival in solid malignancies, such as melanoma,5,6 thus many emerging experimental immunotherapies seek to enhance the tumor’s immunogenicity and increase the anti-tumor CD8+ T cell response.