In Part 1, we look at the original studies that led to the discovery of TNF in two separate labs where researchers were looking for two completely different things. We’ll learn how these discoveries then fueled the use of TNF in the failed trials as an anti-cancer agent, and the eventual development of antibody therapy against TNF in septic shock.

• Intro :11
• The origins of this episode and what we’ll cover here and in Part 2 :18
  • What Part 1 will cover 2:01
    • Early cytokine research in general
    • codiscovery of TNF
    • TNF as anticancer agent
    • TNF’s role in cachexia
    • trials of anti-TNF in the setting of septic shock
  • What part 2 will cover 2:59
    • TNF’s role in rheumatoid arthritis
  • TNF in the late 1800s 3:18
  • Lipopolysaccharide from gram-negative bacteria is first isolated and discovered 8:16
  • Fast forward to the 1960s, enter Memorial Sloan Kettering Cancer Center 9:08
  • Anthony Cerami studies cachexin in his Rockefeller lab 11:10
    • Focus on cachexia 12:27
  • Late 1980s: TNF is produced and given to humans using recombinant technology 20:01
  • Studies of TNF in patients with various types of cancer 20:48
    • High doses seem to induce shock-like illness 21:38
    • TNF-secreting tumor is created and tested 25:21
  • Some take away 26:12
  • Studying TNF led to the discovery that it’s associated with shock 26:33
  • Money pours into research on blocking TNF 27:00
  • A look at studies of TNF in infection 27:22
  • Study of TNF in sepsis 30:20
  • Let’s talk about anti-TNF and what it’s doing 34:00
  • Studies of anti-TNF in humans 36:00
  • Rat and baboon studies don’t always correlate with humans 40:25
  • Episode recap 40:45
  • Stay tuned for Part 2 42:20
  • Follow us on Twitter @HRheuminations and leave us a review in iTunes 42:50

We’d love to hear from you! Send your comments/questions to [email protected]. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum

References:

Beutler B, et al. Science. 1985;229:869–871.

Blick M, et al. Cancer Research. 1987;47:2986-2989.

Carswell E, Williamson B. Cancer Imm. 2012;12:4.

Feldman M. Nat Rev Immunol. 2002;2:364-371.

Fong Y, et al. J Exp Med. 1989;170:1627-1633.

Kawakami M. Mol Med. 2014;doi:10.2119/molmed.2014.00177.

Lv S, et al. Int J Clin Pract. 2014;68:520-528.

Marks JD, et al. Am Rev Respir Dis. 1990;141:94-97.

McCarthy EF. Iowa Orthop J. 2006;26:154-158.

Michi HR, et al. N Engl J Med. 1988;318:1481-1486.

Oliff A. Cell. 1988;54:141-142.

Opal SM, et al. J Infect Dis. 1990;161:1148-1152.

Qui P, et al. Expert Opin Investig Drugs. 2011;20:1555-1564.

Tracey KJ, et al. Nature. 1987;330:662-4.

Waage A, et al. Lancet. 1987;1:355-7.