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Pioneers of Cancer Cell Therapy: Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Genomic Expression, Immuno-Oncology & Genomics, Immunotherapy, Innovation in Immunology Diagnostics, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, Interviews with Scientific Leaders, Investment in Technological Breakthrough, Metastasis Process, Monoclonal Immunotherapy, mtDNA, NK Cell-Based Cancer Immunotherapy, tagged antigen-specific eradication of B-lineage cells, infusion of anti–CD19-CAR-transduced T cells on August 19, 2016| 1 Comment »

Pioneers of Cancer Cell Therapy: Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors

Curator: Aviva Lev-Ari, PhD, RN

Article ID #209: Pioneers of Cancer Cell Therapy: Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors. Published on 8/19/2016

WordCloud Image Produced by Adam Tubman

Chimeric Antigen Receptor T-Cell Therapy: Players in Basic & Translational Research and Biotech/Pharma

The companies are teamed with academic pioneers:

Novartis with University of Pennsylvania;
Kite Pharma with the National Cancer Institute;
Juno Therapeutics with Sloan Kettering,
the Fred Hutchinson Cancer Research Center in Seattle and Seattle Children’s Hospital.

IMAGE SOURCE: National Cancer Institute

“CAR-T cell immunotherapy” – genetically modified T cells that are engineered to target specific tumor antigens and/or genes that are involved in survival, proliferation, and the enhancement of effector functions have been under intense research.

CAR technology was originally reported by Zelig Eshhar in 1993.

https://www.weizmann.ac.il/immunology/sci/EshharPage.html

Prof. Zelig Eshhar, Ph.D., served as Chairman of the Department of Immunology at the Weizmann Institute. Prof. Eshhar has been Chair of Scientific Advisory Board at TxCell S.A. since April 2016. Prof. Eshhar has been a Member of Scientific Advisory Board at Kite Pharma, Inc. since August 8, 2013. Prof. Eshhar served as a Member of Scientific Advisory Board at Intellect Neurosciences, Inc. since April 2006.

Prof. Eshhar pioneered the CAR approach (or T-Body as he termed it) to redirect T cells to recognize, engage and kill patient’s tumor cells by engineering them with a construct that combines the anti-target specificity of an antibody with T cell activation domains. Prof. Eshhar serves on several editorial boards, including Cancer Gene Therapy, Human Gene Therapy, Gene Therapy, Expert Opinion on Therapeutics, European Journal of Immunology and the Journal of Gene Medicine. He was a Research Fellow in the Department of Pathology at Harvard Medical School and in the Department of Chemical Immunology at the Weizmann Institute in Israel. His achievements were recognized by several international awards, most recently the CAR Pioneering award by the ATTACK European Consortium. Prof. Eshhar obtained his B.Sc. in Biochemistry and Microbiology and his M.Sc. in Biochemistry from the Hebrew University, and his Ph.D. in the Department of Immunology from the Weizmann Institute of Science.

http://www.bloomberg.com/research/stocks/people/person.asp?personId=32720993&privcapId=32390485

Zelig Eshhar and Carl H. June honored for research on T cell engineering for cancer immunotherapy

New Rochelle, NY, November 11, 2014–Zelig Eshhar, PhD, The Weizmann Institute of Science and Sourasky Medical Center, and Carl H. June, MD, PhD, Perelman School of Medicine, University of Pennsylvania, are co-recipients of the Pioneer Award, recognized for lentiviral gene therapy clinical trials and for their leadership and contributions in engineering T-cells capable of targeting tumors with antibody-like specificity through the development of chimeric antigen receptors (CARs). Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers, is commemorating its 25th anniversary by bestowing this honor on the leading Pioneers in the field of cell and gene therapy selected by a blue ribbon panel* and publishing a Pioneer Perspective by the award recipients. The Perspectives by Dr. Eshhar and Dr. June are available free on the Human Gene Therapy website at http://www.liebertpub.com/hgt until December 11, 2014.

In his Pioneer Perspective entitled “From the Mouse Cage to Human Therapy: A Personal Perspective of the Emergence of T-bodies/Chimeric Antigen Receptor T Cells” Professor Eshhar chronicles his team’s groundbreaking contributions to the development of the CAR T-cell immunotherapeutic approach to treating cancer. He describes the method’s conceptual development including initial proof-of-concept, and the years of experimentation in mouse models of cancer. They first tested the CAR T-cells on tumors transplanted into mice then progressed to spontaneously developing cancers in immune-competent mice, which Dr. Eshhar describes as “a more suitable model that faithfully mimics cancer patients.” He recounts successful antitumor effects in mice with CAR modified T-cells injected directly into tumors, with effects seen at the injection site and at sites of metastasis, and even the potential of the CAR T-cells to prevent tumor development.

Dr. Carl H. June has led one of the clinical groups that has taken the CAR therapeutic strategy from the laboratory to the patients’ bedside, pioneering the use of CD19-specific CAR T-cells to treat patients with leukemia. In his Pioneer Perspective, “Toward Synthetic Biology with Engineered T Cells: A Long Journey Just Begun” Dr. June looks back on his long, multi-faceted career and describes how he combined his knowledge and research on immunology, cancer, and HIV to develop successful T-cell based immunotherapies. Among the lessons Dr. June has embraced throughout his career are to follow one’s passions. He also says that “accidents can be good: embrace the unexpected results and follow up on these as they are often times more scientifically interesting than predictable responses from less imaginative experiments.”

“These two extraordinary scientists made seminal contributions at key steps of the journey from bench to bedside for CAR T-cells,” says James M. Wilson, MD, PhD, Editor-in-Chief of Human Gene Therapy, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.

SOURCE

http://www.eurekalert.org/pub_releases/2014-11/mali-ze111114.php

The General procedure of CAR-T cell therapy involves the follwoing steps:

1) Separate T cells from patient;

2) Engineer these T cells to express an artificial receptor, which is called “CAR” that usually targets tumor-specific antigen;

3) Expand the CAR T cells to a sufficient amount;

4) Re-introduce the CAR T cells to patient.

There are two major components that are critical to the CAR-T cell immunotherapy:

the design of CAR itself and
the choice of the targeted tumor specific antigen.

SOURCE

http://www.ochis.org/node/209

First publication on Adoptive transfer of genetically modified T cells is an attractive approach for generating antitumor immune responses

Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19

James N. Kochenderfer, , John E. Janik, Mark E. Dudley, Maryalice Stetler-Stevenson, Steven A. Feldman, Irina Maric, Mark Raffeld, Debbie-Ann N. Nathan, Brock J. Lanier, Richard A. Morgan, Steven A. Rosenberg

Blood 2010 116:4099-4102; doi:10.1182/blood-2010-04-281931

Abstract

Adoptive transfer of genetically modified T cells is an attractive approach for generating antitumor immune responses. We treated a patient with advanced follicular lymphoma by administering a preparative chemotherapy regimen followed by autologous T cells genetically engineered to express a chimeric antigen receptor (CAR) that recognized the B-cell antigen CD19. The patient’s lymphoma underwent a dramatic regression, and B-cell precursors were selectively eliminated from the patient’s bone marrow after infusion of anti–CD19-CAR-transduced T cells. Blood B cells were absent for at least 39 weeks after anti–CD19-CAR-transduced T-cell infusion despite prompt recovery of other blood cell counts. Consistent with eradication of B-lineage cells, serum immunoglobulins decreased to very low levels after treatment. The prolonged and selective elimination of B-lineage cells could not be attributed to the chemotherapy that the patient received and indicated antigen-specific eradication of B-lineage cells. Adoptive transfer of anti–CD19-CAR-expressing T cells is a promising new approach for treating B-cell malignancies. This study is registered at www.clinicaltrials.gov as #NCT00924326.

SOURCE

http://www.bloodjournal.org/content/116/20/4099

According to Setting the Body’s ‘Serial Killers’ Loose on Cancer

After a long, intense pursuit, researchers are close to bringing to market a daring new treatment: cell therapy that turbocharges the immune system to fight cancer.

By ANDREW POLLACK AUG. 1, 2016

http://www.nytimes.com/2016/08/02/health/cancer-cell-therapy-immune-system.html?_r=0

Dr. June’s 2011 publications did not cite Dr. Rosenberg’s paper [Blood, 2010] from the previous year, prompting Dr. Rosenberg to write a letter to The New England Journal of Medicine. Dr. June’s publications also did not acknowledge that the genetic construct he had used was the one he had obtained from Dr. Campana of St. Jude.

St. Jude sued the University of Pennsylvania. Novartis sided with Penn, and Juno Therapeutics with St. Jude.

The suit was settled last year, with Novartis agreeing to pay $12.25 million plus possible future payments and royalties. Within days, Dr. June sent a correction and letter of regret to The New England Journal of Medicine, acknowledging that the CAR used in his groundbreaking 2011 study, and in treating Emily Whitehead, was “designed, developed and provided” by St. Jude.

Dr. Sadelain was not alone in this work. Zelig Eshhar, an Israeli scientist, is credited with developing one of the first crude CARs around 1989. Dr. Rosenberg, always on the lookout for new types of immunotherapy, invited Dr. Eshhar to be a visiting scientist in his laboratory at the National Cancer Institute.

Another early developer was Dr. Dario Campana of St. Jude Children’s Research Hospital.

Douglas Green, who was one of Dr. Sadelain’s doctoral thesis advisers and is now chairman of immunology at St. Jude Children’s Research Hospital.

But Dr. Sadelain, he continued, “believed in his approach and he pursued it relentlessly.”

After earning his Ph.D., Dr. Sadelain headed for the Whitehead Institute for Biomedical Research in Cambridge, Mass., to learn how to do gene therapy, using disabled viruses that could not cause disease to deliver genes into cells. By 1992, he had demonstrated that he could genetically engineer mouse T-cells.

He then moved to Sloan Kettering. In 2003, he and his colleagues — including his partner and now wife, Isabelle Rivière — showed that genetically engineered T-cells could eradicate certain cancers in mice.