The Immune Response Corporation

The Immune Response Corporation (IRC) pioneered immunotherapeutic products. The firm was founded by Jonas Salk and Kevin Kimberlin when Kimberlin, who asked Salk to become lead scientific advisor for a new biotech company specializing in ‘anti-idiotypes,’ a novel vaccine technology,”[1] Salk called the proposal “liberating.”[2]

Overview

Francis Crick once said about Salk, “Few have made one discovery that has benefited humanity so greatly. Jonas was a man who, right to his last day, was actively in pursuit of another.”[3] That pursuit was The Immune Response Corporation.

The management team included CEO Jim Glavin, former CEO of Genetic Systems (acquired by Bristol Myers) and Chief Scientific Officer, Dennis Carlo, a former Vice President of R&D at Hybritech.[4] Joe O'Neill was recruited CEO in 2005,[5] because of his work as the chief architect of the President's Emergency Plan for AIDS Relief, known as PEPFAR.[6][7][8] Corporate partners that support IRC include The Rorer Group, Rhone Poulenc, The Pasteur Institute, Institute Merieux, NovaRx, Agouron Pharmaceuticals, Bayer, and Pfizer. The company went public in 1990 and in 1991 its stock outperformed every other public stock in the U.S. according to Barron’s: “hands down the most astounding stock in 1991 was Immune Response which rose 1,265 percent.”

Products

Cancer Immunotherapy

The company's anti-idiotype program had a significant impact on the ultimate acceptance and success of cancer immunotherapy. It was based on research by Belgian biologist, Jacques Urbain,[9] whom Kimberlin retained, and who reported to Jonas Salk. Dr. Urbain's idiotypic research showed a “dramatic enhancement of an antiviral immune response by dendritic cells,” thus demonstrating the principle of a dendritic cell-enhanced immunity by means of anti-idiotype antibodies.[10] He followed up with an anti-idiotype tumor vaccine against lymphocytes “not normally recognized” by the immune system.[11] The Immune Response Corporation filed a patent on this invention entitled: “Idiotypic Vaccination Against B-Cell Lymphoma” in May 1990.[12][13] IRC described the vaccination treatment as utilizing antigen-presenting dendritic cells to stimulate responses to tumor antigens. Preclinical studies published in 1994 in the European Journal of Immunology demonstrated that 8 out of 10 of the treated rats survived post-treatment, whereas the 10 control rats died.[14] Nature Medicine later reported on  an independent group of scientists at Stanford University who published results of a Phase I clinical trial using this technology to treat patients suffering from B-cell lymphoma.[15]

After incubation and pre-clinical validation by IRC, the dendritic cell product was licensed to a startup in exchange for founders stock, $500,000 in cash and royalties.[16] Recognizing the potential for antigen-presenting dendritic cells, that startup changed its name to Dendreon.[17] Its major investor was Paul Allen[18] (Vulcan Ventures owned 22% of the company by the time it went public). Allen had been diagnosed with non-Hodgkin's disease, often a precursor to B-cell lymphoma, the subject of the IRC/Urbain invention. Based that invention on positive clinical results, this product, Sipuleucel-T, more commonly known as Provenge, became the first FDA-approved immunotherapeutic cancer vaccine.[19][20]

Scientific American[21] and CNN[22] were among the first to identify this as a landmark vaccine and a milestone.

Sipuleucel-Ti, initially approved for treating patients with metastatic prostate cancer that has not responded to hormone therapy,[23] was then recommended in 2015 by the National Comprehensive Cancer Network as a first-line treatment for patients with metastatic Castration Resistant Prostate Cancer.[24] According to its manufacturer, the Sanpower Group, more than 30,000 men had been prescribed Sipuleucel-T as of 2017.[25]

After its U.S. market introduction, the process and facility that produced this immunotherapeutic became the key to the approval of Kymriah was the first CAR-T immunotherapy (chimeric antibody receptor T-Cell).[26] Its developer, Novartis, required a complex manufacturing infrastructure capable of delivering an immunotherapeutic of consistent quality in order to produce the clinical and commercial quantities needed to obtain FDA approval.[27] “Luckily, one biotech, Dendreon, solved this problem with its prostate cancer treatment,” as stated in Forbes Magazine.[27] Since the team running the manufacturing facility were experts at producing and distributing the only commercially available cancer immunotherapy, Novartis purchased the process and the FDA-approved facility and hired 100 people who were making the prostate cancer immunotherapy.[26][28] Approved by the Food and Drug Administration (FDA) on August 13, 2017, Kymriahwas the world’s first gene therapy to reach the market,[29] an approval that was recognized by FDA Commissioner Scott Gottlieb with these remarks: “Today marks another milestone in the development of a whole new scientific paradigm of the treatment of serious diseases…We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer.”[30]

HIV Immunotherapeutic

The AIDS immunotherapy sponsored by IRC was based a hypothesis of Jonas Salk's, published in Nature, “Prospects for the Control of AIDS through Immunization of Seropositive Individuals.”[31]

Designed to help HIV-infected patients mount a more vigorous immune response, it was rooted in the principle of non-infectious viral immunization pioneered by Dr. Salk in his influenze and polio vaccines, both standards throughout the world today. Other companies at the time were testing HIV therapies but none “moved more aggressively toward large-scale human trials” according to an article in The New York Times.[32] For example, IRC applied for trial approval, and within 35 days, in November, 1987, sponsored the first HIV vaccine trial on humans “under a 1987 law that allows California researchers to test new AIDS therapies without seeking federal approval.”[33] The subsequent Phase III trial, Study 806, was the first-ever large-scale trial to study an immune-based therapy.[34] Enrolling 2,527 patients, it was a random, placebo-controlled trial to assess the HIV immune therapy in combination with antiviral drugs. The end point was slowing the progression to AIDS or death for patients having CD4 T-cells between 300 and 549 cells/mm.[35]

Bruce Walker commented on the outcome of Study 806. Walker was the director of the Harvard Medical School division of AIDS at Massachusetts General Hospital, the largest teaching hospital for Harvard Medical School. He wrote, “The study was stopped prematurely due to the decrease in AIDS-related illness resulting from the introduction of more effective antiviral drug combinations. In addition, the study was not well controlled. Participants differed in terms of the antiviral medications during the course of that study, making interpretation of the findings problematic.” The problematic outcome adversely impacted funding, and so, after raising $350 million, the Company abandoned the project and liquidated its assets in 2008.  Nonetheless, Walker recognized this as “the first clear demonstration of the potential reconstitution of the immune response in chronic HIV infection…This is the first proof of the principle that therapeutic vaccination can help people with chronic HIV infection mount a strong CD4 helper cell response.”[36]   

References
  1. Nobile, Philip. “Jonas Salk’s Quest for an AIDS Vaccine.” Village Voice.  October 23, 1990 Vol XXXV No. 43. verification: University of California San Diago Library, https://library.ucsd.edu/speccoll/findingaids/MSS0001_BLR.pdf.%5B%5D
  2. Charlotte, Jacobs, Jonas Salk : a life, Ward, Pam, ISBN 978-1504663083, OCLC 919967060
  3. Sherrow, Victoria.  “Jonas Salk, Beyond the Microscope.” Revised Edition. Chelsea House Publisher 2008. P 112.
  4. The Immune Response Corporation, Registration Statement filed with The Securities Exchange Commission. October 28, 1996. Pg 35.
  5. "Joseph F. O'Neill, M.D., Former Director of the Office of National AIDS Policy, Joins The Immune Response Corporation as CEO and President". Retrieved 2018-10-08.
  6. Caryl, Christian (February 14, 2013). "What George W. Bush Did Right". Foreign Policy.
  7. Plaut, Martin (January 16, 2009). "Has Bush Been Africa's Best Friend?". BBC News.
  8. "AIDS Battle Burnishes Bush's Legacy in Africa". NBC News. 2009-01-11.
  9. , Bohlen, Heribert; Jacques Urbain & Kristiaan Thielemans, "Idiotypic Vaccination Against B Cell Lymphoma", issued 1991/09/20. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO1991013632&redirectedID=true
  10. Francotte, M.; Urbain, J. (1 December 1985). "Enhancement of antibody response by mouse dendritic cells pulsed with tobacco mosaic virus or with rabbit antiidiotypic antibodies raised against a private rabbit idiotype". Proceedings of the National Academy of Sciences. 82 (23): 8149–8152. Bibcode:1985PNAS...82.8149F. doi:10.1073/pnas.82.23.8149. PMC 391460. PMID 3877936.
  11. Ellis, Ronald W. "Vaccines: New Approaches to Immunological Problems". Pg 336.
  12. WO/1991/013632, Bohlen, Heribert; Jacques Urbain & Kristiaan Thielemans, "Idiotypic Vaccination Against B Cell Lymphoma", issued 1991/09/20. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO1991013632&redirectedID=true
  13. The Securities and Exchange Commission, Registration Statement for The Immune Response Corporation. 10.28.96. Pgs 29-31. https://www.nasdaq.com/markets/ipos/filing.ashx?filingid=465620
  14. The Securities and Exchange Commission. Registration Statement for The Immune Response Corporation. 10.28.96. Pg 3029-31.
  15. Hsu, Frank J.; Benike, Claudia; Fagnoni, Francesco; Liles, Tina Marie; Czerwinski, Debra; Taidi, Behnaz; Engleman, Edgar G.; Levy, Ronald (January 1996). "Vaccination of patients with B–cell lymphoma using autologous antigen–pulsed dendritic cells". Nature Medicine. 2 (1): 52–58. doi:10.1038/nm0196-52. PMID 8564842.
  16. Research, Center for Biologics Evaluation and. "Approved Products - Questions and Answers - Provenge". www.fda.gov. Retrieved 2018-10-18.
  17. "History". Dendreon.
  18. "Business | Vulcan Backs Biotech Firm Dendreon With $10 Million | Seattle Times Newspaper". community.seattletimes.nwsource.com. Retrieved 2018-10-18.
  19. Landau, Elizabeth. "'Landmark' cancer vaccine gets FDA approval". CNN. Retrieved 2018-10-18.
  20. &NA; (2006). "Sipuleucel-T". Drugs in R & D. 7 (3): 197–201. doi:10.2165/00126839-200607030-00006. ISSN 1174-5886.CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  21. Rex, Erica (June 24, 2010). "Vaccines Derived from Patients' Tumor Cells Are Individualizing Cancer Treatment". Scientific American.
  22. Landau, Elizabeth (April 29, 2010). "'Landmark' cancer vaccine gets FDA approval". CNN.
  23. "Search Detail page". Clinical Trials.
  24. National Comprehensive Cancer Network . 2016. NCCN Clinical Practice Guidelines in Oncology (NCCN Guideline®): Prostate Cancer: Version 1. 2015 November 10. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
  25. "PROVENGE to benefit from State Council meeting decision_Main Articles_News_The Sanpower Group". en.sanpowergroup.com.
  26. Herper, Matthew (May 7, 2014). "Is This How We'll Cure Cancer?". Forbes.
  27. Herper, Matthew (May 7, 2014). "Is This How We'll Cure Cancer?". Forbes.
  28. "UPDATED: Novartis buys Dendreon New Jersey plant | FiercePharma". www.fiercepharma.com. Retrieved 2018-10-09.
  29. Mukherjee, Sy. “The Way We Treat Cancer Will Be Revolutionized As Gene Therapy Comes to the U.S”. Fortune Magazine. August 30, 2017.
  30. "Press Announcements - FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma". www.fda.gov. U.S. Food & Drug Administration. October 18, 2017.
  31. Salk, Jonas (June 1987). "Prospects for the control of AIDS by immunizing seropositive individuals". Nature. 327 (6122): 473–476. Bibcode:1987Natur.327..473S. doi:10.1038/327473a0. PMID 3587367.
  32. Johnson, George (November 25, 1990). "Once Again, A MAN WITH A MISSION". The New York Times.
  33. "AIDS Experiment Based on Salk's Theories". The New York Times. February 12, 1988.
  34. Martinez, L. Joel (December 2000). "Remune Rejected: Will a Manual Recount Be Required?". The Center for AIDS Information & Advocacy.
  35. Kahn, James O.; Cherng, DW; Mayer, K; Murray, H; Lagakos, S (1 November 2000). "Evaluation of HIV-1 Immunogen, an Immunologic Modifier, Administered to Patients Infected With HIV Having 300 to 549 × 106/L CD4 Cell Counts: A Randomized Controlled Trial". JAMA. 284 (17): 2193. doi:10.1001/jama.284.17.2193. PMID 11056590.
  36. Walker, Bruce, AIDS Vaccine Induces HIV-specific Immune Response In Chronic Infection, Massachusetts General Hospital, published in Science News, May 26, 2003, https://www.sciencedaily.com/releases/2003/05/030526104653.htm
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