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Not one but several problems hobble Cytokine therapy in cancer.

Small, soluble, typically secreted but also membrane-bound, cytokines are a key effector arm of the immune system. By binding to surface receptors on cells, cytokines trigger a variety of biochemical cascades that ultimately alter gene expression within those cells.

Cytokine binding to their receptors is very high affinity, which explains their profound biological effects even at very low concentrations. Their biological effects primarily but not solely on lymphocytes, it isn’t a stretch to postulate that cytokines can regulate the A-to-Z of a responding cell’s physiology by influencing its differentiation, proliferation, migration.

Drawbacks Of Cytokine Therapies For Cancer

  • Though cytokines are extremely potent, for the most part Nature seems to have designed them to work locally. Thus, they inherently have short half-lives, something that necessitates prolonged administration.
  • Major problem is how to maintain effective cytokine dose over a prolonged time period. This becomes even more of a problem when a cytokine’s given systemically.
  • Given that cytokines are not just potent but rather pluripotent, prolonged administration brings with it the cost of undesirable side effects, even more of a concern when given systemically. Some of these effects can even be unpredictable since so much more of cytokine biology is deciphered using mouse models that often translate poorly to human biology.
    • Human Interleukin 12 clinical trial history offers an extremely pertinent case in point. With its potent effect against tumors, IL-12 is perhaps a prototypic anti-cancer cytokine. No surprise then that all the way back in 1995, in partnership with Wyeth, https://en.wikipedia.org/wiki/Ge…. was testing systemic IL-12 in renal cell carcinoma patients. 12 of 17 patients suffered severe toxicity, needing to be hospitalized, with 2 deaths (1). Dosing and sequence of dosing turned out be key weaknesses of this study (2). However, this early setback was also a warning sign that cytokine therapies for cancer would likely involve a long, hard slog which indeed they have proven to be.
  • Cytokine therapy for cancer thus needed several years of back to the drawing board. In the interim, cancer immunotherapy improved by leaps and bounds in the one area where cytokine therapy can’t possibly improve and which may perhaps be its biggest drawback, lack of specificity. After all, unlike tumor antigen-specific T cells and monoclonal antibodies (mAbs), not being antigen-specific, cytokines are and can only ever be blunt instruments, akin to swatting a fly with a hammer. Thus, newer cytokine therapy approaches naturally fit in as adjuncts in this new cancer immunotherapy landscape (see below from 3 for approaches in general and from 4 for approaches for IL-12 in particular).
  • Meantime a variety of technological approaches are now also being tested to improve cytokine half-lives and their ability to more efficiently target tumors. One of the most straightforward and technically simpler approach to increase a cytokine’s half-life is to PEG-ylate it, i.e., conjugate the cytokine molecules to Polyethylene glycol (PEG). However, advances in technology make it just one of many approaches currently under test in pre-clinical animal models and clinical trials (see figure below from 5).

Despite such improvements, cytokine therapy’s still fraught with risk as we can surmise from Ziopharm Oncology’s recent Glioblastoma clinical trial death (6). Ziopharm Oncology’s approach consists of using adenovirus as the vector (carrier). Cargo it’s engineered to carry and deliver is human IL-12, designed to be conditionally expressed using a non-steroidal analog of the insect hormone ecdysone such that default IL-12 expression is low but capable of high inducibility in response to oral delivery of the specific heterodimerizer drug INX-1001 (veledimex) (5).

Cytokines Currently (mid-2016) Approved For Cancer Therapies

  • In 1992, the US FDA approved IL-2 as a single agent for metastatic renal cell carcinoma and in 1998 for metastatic melanoma (7).
  • PEG-ylated IFN-alpha is safer and requires less frequent dosing. The FDA approved it as adjuvant treatment for high-risk Stage III melanoma (8, 9).
    • A meta-analysis showed IFN-alpha’s significant association with disease-free survival in 10 of 17 multi-institutional clinical trials and improved overall survival in 4 of 14 comparison studies (10).
    • IFN-alpha is also approved for
      • Hematologic malignancies such as AIDS-related Kaposi’s sarcoma.
      • Advanced renal cancer as a component with the anti-angiogenic Bevacizumab.
  • In 1991, the US FDA approved recombinant Granulocyte macrophage colony-stimulating factor (GM-CSF) for acute myelogenous leukemia, not for its direct anti-tumor effect but to shorten the time for neutrophil recovery and help reduce risk of infections following induction chemotherapy (11).

Bibliography

1. Leonard, John P., et al. “Effects of single-dose interleukin-12 exposure on interleukin-12–associated toxicity and interferon-γ production.” Blood 90.7 (1997): 2541-2548. https://www.researchgate.net/pro…

2. Cohen, Jon. “IL-12 deaths: explanation and a puzzle.” Science 270.5238 (1995): 908-908.

3. Petrozziello, Elisabetta, Tabea Sturmheit, and Anna Mondino. “Exploiting cytokines in adoptive T-cell therapy of cancer.” Immunotherapy 7.5 (2015): 573-584.

4. Hernandez-Alcoceba, Ruben, et al. “Gene therapy approaches against cancer using in vivo and ex vivo gene transfer of interleukin-12.” Immunotherapy 8.2 (2016): 179-198.

5. Tugues, S., et al. “New insights into IL-12-mediated tumor suppression.” Cell Death & Differentiation 22.2 (2015): 237-246. http://www.nature.com/cdd/journa…

6. GEN News Highlights, July 15, 2016. Ziopharm Confirms 3 Patient Deaths in Gene Therapy Trial | GEN News Highlights | GEN

7. Rosenberg, Steven A. “IL-2: the first effective immunotherapy for human cancer.” The Journal of Immunology 192.12 (2014): 5451-5458. https://www.roswellpark.edu/site…

8. Eggermont, Alexander MM, et al. “Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.” The Lancet 372.9633 (2008): 117-126. https://www.researchgate.net/pro…

9. Bottomley, Andrew, et al. “Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma: a phase III randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group.” Journal of clinical oncology 27.18 (2009): 2916-2923. Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation in Resected Stage III Melanoma: A Phase III Randomized Controlled Trial of Health-Related Quality of Life and Symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group

10. Mocellin, Simone, et al. “Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis.” Journal of the National Cancer Institute 102.7 (2010): 493-501. A Systematic Review and Meta-analysis

11. Lee, Sylvia, and Kim Margolin. “Cytokines in cancer immunotherapy.” Cancers 3.4 (2011): 3856-3893. http://www.mdpi.com/2072-6694/3/…

https://www.quora.com/What-are-the-limits-of-cytokine-therapies-for-tumor-treatment-Also-does-local-administration-of-cytokines-outperform-systemic-administration/answer/Tirumalai-Kamala

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