Page 19 - Read Online

Page 2 of 9 Ashdown. J Cancer Metastasis Treat 2022;8:6 https://dx.doi.org/10.20517/2394-4722.2022.01

In 2008, the United States Presidential Report on Cancer stated, “The toll of cancer has become simply an
awful part of life; incidence is rising for several cancers; the most intransigent of malignancies remain
impervious to treatment; (and) an absolute cure remains elusive”. The report further added, “Despite
declaring a national war on cancer in 1971 and investing many billions of dollars since then to understand and
defeat cancer, our success against the disease in its many forms has been uneven and unacceptably slow” .
[2]
Previously in 1996, Director of the Pittsburgh Cancer Centre Michael Lotze said, “Mono and multi-agent
chemotherapy just do not work in many settings, we should have dispensed with these notions years ago” .
[3]
This echoed the sentiment in Scientific American in a previous 1994 article entitled A War Not Won
“Despite dramatic scientific gains, cancer remains an undaunted killer” .
[4]

Clearly, these sorts of concerns led Laurence Baker, MD, senior US oncologist and Chairman of the
Southwest Oncology Group (SWOG) to state in 2010 in the Journal of the National Cancer Institute (JNCI) “
A cure is the expectation of society, we are not taking that seriously enough; We have a system that doesn’t
even really try to meet that expectation; I am trying to get people to stop saying how successful the cancer
research enterprise is. It is not true. It is just not true” .
[5]
Even today, in the midst of a “transformative” immunotherapy era of checkpoint inhibitor therapy, only a
minority of patients derive benefits and at the cost of substantial biological and financial toxicity. Despite
these negative and troubling historic comments, there is room for optimism.

“Nature often gives us hints to her profoundest secrets” - William B Coley [6]
For more than a century and since William Coley and his bacterial toxins, the notion that the immune
system can be harnessed to treat cancer has met with limited and sporadic clinical success and much
controversy . And like cancer therapy today, it has been hit and miss. Those occasional spectacular
[7]
“miracles” under various “immune tweaking” treatment modalities has intrigued clinicians and scientists
alike and fuelled the relentless enthusiastic pursuit to make these random minority of successes and long
term survival a reality in most patients. How can we translate/duplicate/amplify the efficacy at least seen in
the mouse experiments? A broad explanation of why these sporadic successes occur infrequently was
articulated by Prof Lloyd Old in 1993.

“
Why hasn’t Coley’s approach been forged into a widely available therapy with a predictable benefit for cancer
patients? The best reason is, - the cellular and molecular language of inflammation and immunity had to be
understood before the forces that Coley unleashed could be predictably translated into tumor cell destruction”.
[7]
- Lloyd Old 1993 .
His words back then actually described the way forward, detailed aspects of which are in the process of
being elucidated today for clinical utility. Clearly, the correct sequence of therapeutic events already
happens, at least randomly in some patients, even with the crudest approaches such as those used by Coley.
The fundamental understanding (language) of the intimate interactions of the tumour with the immune
system, particularly in the tumour microenvironment (TME), is providing answers to why some very
different modalities can work effectively but only occasionally.

The cellular and molecular language of inflammation and immunity
A major advance in recent years has been the realisation that the immune system is not ignorant to the
presence of cancer, and in particular, the cellular interactions of the TME collectively are “shielding” the
[8]
cancer from immune destruction . Specifically, the immune system is suppressing itself, tolerant to the