MEDI4736 trials - for esophageal cancer - 1262200

Hello Jim,

Thanks for sending Dr. West's link.

I was reading about the potential for a new human clinical trail working with CD-47 antibodies lead by Stanford University:

http://stemcell.stanford.edu/CD47

Thoughts?

Bill

Hello Janine,

Thanks for connecting with me. I just found GRACE today.

Here is a small blurb on MEDI4736 that I gleaned from my web search:

AMSTERDAM – A standing-room-only crowd filled a drug development session at the European Cancer Congress 2013 to hear the latest phase I data.

Highlights included information on the programmed cell death ligand 1 (PD-L1) blocking monoclonal antibody MEDI4736, which showed clinical activity over multiple doses in 11 heavily pretreated patients (median four prior therapies) with non–small cell lung cancer (NSCLC), melanoma, and colorectal cancer.

Twice-weekly intravenous dosing decreased tumor burden by 42%-83%, with some responses seen after just 6 weeks, reported Dr. Samir Khleif, director of the Georgia Regents University Cancer Center, Augusta. Four of 10 evaluable patients had partial responses (1 unconfirmed), and 2 had stable disease in the study.

Tolerability was particularly good, with no deaths, dose-limiting toxicities, treatment-related grade 3/4 adverse events, or pneumonitis or colitis of any grade, he reported at the multidisciplinary European cancer congresses.

Invited discussant Dr. Filippo de Braud, director of medical oncology at the Fondazione IRCCS National Cancer Institute, Milan, also highlighted the low toxicity profile and said MEDI4736 produced a reasonable number of responses in an unselected patient population. Still, the PD-L1 antibody is entering a crowded field, and early evidence with ipilimumab and nivolumab suggests that combined immunotherapy will be the way forward to boost responses.

"Any kind of combination is going to be complicated, but we need to start thinking about how to select patients," he said.

Thanks for your insights Dr. Weiss,

This is the MEDI4736 trail that I am being screened for at Memorial Sloan Kittering:

http://clinicaltrials.gov/ct2/show/NCT01693562

Esophageal Cancer

IMMUNOTHERAPY FOR ESOPHAGEAL CANCER

Several approaches to immunotherapy for esophageal cancer have shown promise in early clinical trials. These treatments can be broken into 6 main categories: checkpoint inhibitors/immune modulators, therapeutic vaccines, adoptive T cell transfer, monoclonal antibodies, adjuvant immunotherapies, and cytokines.

Checkpoint Inhibitors
Checkpoint Inhibitors / Immune Modulators

A promising avenue of clinical research in esophageal cancer is the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses. Several checkpoint inhibitors, targeting multiple different checkpoints, are currently in development.
Nivolumab (ONO-4538) is an anti-PD-1 antibody being developed by ONO/Bristol-Myers Squibb that is in a phase II trial for patients with advanced esophageal cancers (JapicCTI-142422).
MEDI4736, a PD-L1-targeting antibody made by MedImmune/AstraZeneca, is being tested in a phase I/II trial for patients with advanced solid tumors (NCT01693562).
Pembrolizumab (Keytruda®, MK-3475) is an anti-PD-1 antibody being developed by Merck that is in a phase I trial for patients with advanced, biomarker-positive solid tumors (NCT02054806).
MPDL3280A, an anti-PD-L1 antibody being developed by Roche/Genentech, is being tested in numerous cancers in a phase I trial (NCT01375842).
A phase I trial of MPDL3280A in combination with bevacizumab (Avastin) or chemotherapy is enrolling patients with advanced cancer (NCT01633970).
Urelumab (BMS-663513, anti-4-1BB/CD137), made by Bristol-Myers Squibb, is being tested in a phase I trial in patients with advanced cancers (NCT01471210).
PF-05082566 is an anti-4-1BB/CD137 antibody developed by Pfizer that is being tested in

Combination checkpoint trials include:
A phase I study of lirilumab (anti-KIR antibody; Bristol-Myers Squibb) in combination with nivolumab (anti-PD-1 antibody; BMS) in patients with advanced solid tumors (NCT01714739).
A phase I trial of ipilimumab (Yervoy®), an anti-CTLA-4 antibody, plus Gleevec (imatinib mesylate), a c-Kit inhibitor, for patients with advanced cancer (NCT01738139).
A phase I trial of BMS-986016 (an anti-LAG-3 antibody) with or without nivolumab (Opdivo®) for patients with solid tumors (NCT01968109).
A phase I study of MSB0010718C, an anti-PD-L1 antibody being developed by EMD Serono, in solid tumors, including esophageal cancer (NCT01772004).

Therapeutic Vaccines

Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Several trials of vaccines, given alone or with other therapies, are currently enrolling patients:
A phase II trial of a vaccine that targets the NY-ESO-1 protein in patients with advanced cancer whose cancers express NY-ESO-1 (NCT01697527).
A phase I/II trial with an adjuvant tumor lysate vaccine and the adjuvant ISCOMATRIX in patients with esophageal cancer (NCT02054104).
A phase I/II trial of DCVax in patients with solid tumors (NCT01882946).
A phase I trial of a vaccine (FANG) that blocks furin protein production, plus GM-CSF, for advanced cancer (NCT01061840).
A phase I trial of NY-ESO-1 fusion protein vaccine in patients with advanced cancer whose cancers express NY-ESO-1 (NCT01522820).
A phase I trial testing a tumor cells vaccine and the adjuvant ISCOMATRIX with chemotherapy in patients with advanced cancer after tumor removal (NCT01341496).
A phase I study of tumor cell vaccines with ISCOMATRIX adjuvant and celecoxib in patients undergoing resection of their esophageal cancer (NCT01258868).

Adoptive T Cell Therapy

Another major avenue of immunotherapy for esophageal cancer is adoptive T cell transfer. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response. Several trials of adoptive T cell transfer techniques are currently under way for patients with esophageal cancer, including:
A phase II trial taking enriched tumor-infiltrating immune cells and re-infusing them in patients with metastatic digestive tract cancers, including esophageal cancer (NCT01174121).
A phase II study of T cells genetically reengineered to target the NY-ESO-1 antigen in patients with NY-ESO-1-positive cancers (NCT01967823).
A phase I/II trial of T cells genetically reengineered to target the anti-MAGE-A3-DP4 protein in advanced cancer (NCT02111850).
A phase I/II study of chimeric antigen receptor (CAR) T cells designed to target VEGFR2 (NCT01218867).

Monoclonal Antibodies

Monoclonal antibodies (mAbs) are molecules, generated in the lab, that target specific antigens on tumors. Many mAbs are currently used in cancer treatment, and some appear to generate an immune response. Several mAbs are currently being tested in clinical trials:
A phase II trial of MM-111, a bispecific antibody that binds to HER2 and HER3, in patients with esophageal and gastroesophageal junction cancers (NCT01774851).
A phase I/II trial testing IMMU-132, an antibody-drug conjugate targeting Τrop-2, in patients with esophageal and other cancers (NCT01631552).
A phase I trial of ontuxizumab (MORAb-004), an antibody targeting endosialin/TEM1, in young patients with solid tumors (NCT01748721).
A phase I trial of OMP-52M51, anti-Notch1 monoclonal antibody, in patients with solid tumors (NCT01778439).
A phase I trial of ABT-700, an anti-C-met antibody, in patients with solid tumors (NCT01472016).
A phase I trial of MM-151, an antibody designed to bind and inhibit signaling from EGFR, in patients with solid tumors (NCT01520389).
A phase I trial of CEP-37250/KHK2804, an antibody targeting glycolipids, in patients with advanced solid tumors (NCT01447732).

Adjuvant Immunotherapies

Adjuvants are substances that are either used alone or combined with other immunotherapies to boost the immune response. Some adjuvant immunotherapies use ligands—molecules that bind to proteins such as receptors—to help control the immune response. These ligands can be either stimulating (agonists) or blocking (antagonists).
A phase I trial of entolimod (CBLB502), a recombinant Toll-like receptor 5 (TLR5) agonist, in patients with locally advanced or metastatic solid tumors that cannot be removed by surgery (NCT01527136).

Cytokines

Cytokines are messenger molecules that help control the growth and activity of immune system cells.
A phase I trial testing interleukin 15 (IL-15) in patients with advanced cancer (NCT01572493).
A phase I trial to test interleukin 12 (IL-12) in patients with solid tumors (NCT01417546).
Go to our Clinical Trial Finder to find clinical trials of immunotherapies for esophageal cancer that are currently enrolling patients.

CRI CONTRIBUTIONS AND IMPACT

CRI researchers analyzed NY-ESO-1 cancer-testis (CT) antigen expression in esophageal cancer and have sought to correlate this expression with disease stage and clinical outcome. Although NY-ESO-1 was isolated from an esophageal carcinoma patient, its expression in this type of cancer and its immunogenicity in esophageal cancer patients have not yet been fully elucidated. One hundred twenty three esophageal cancer specimens were analyzed for the expression of NY-ESO-1, and it was expressed in 41 of 123 (33%) esophageal cancer specimens. The high expression frequency of NY-ESO-1 indicates this as a feasible vaccine target in esophageal cancer.
Clinical investigator Eiichi Nakayama, M.D., and colleagues at Okayama University Graduate School of Medicine and Dentistry in Japan reported in the International Journal of Cancer that a vaccine composed of the NY-ESO-1f long peptide administered with the immune stimulants Montanide ISA-51 and Picibanil OK-432 could elicit integrated immune responses including antibodies, CD4+ helper T cells, and CD8+ killer T cells in nine out of the ten patients enrolled in a phase I clinical trial. Three patients, two with lung cancer and one withesophageal cancer, showed stable disease. According to investigators, the immune responses were comparable to or stronger than those reported with various NY-ESO-1 protein vaccines, suggesting that vaccines using long peptides may be a promising approach to therapeutic cancer vaccination against the NY-ESO-1 antigen.
Sources: ACS Facts and F