Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy

J Exp Med (2013) 210 (11): 2223–2237.

Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.

https://rupress.org/jem/article/210/11/ ... ry-induced

“Middle age”
PSYCHOLOGY



Middle age, period of human adulthood that immediately precedes the onset of old age. Though the age period that defines middle age is somewhat arbitrary, differing greatly from person to person, it is generally defined as being between the ages of 40 and 60. The physiological and psychological changes experienced by a middle-aged person centre on the gradual decline of physical abilities and the awareness of mortality. In middle age, the relative potencies of past, present, and future are altered as the individual increasingly directs effort to the process of reminiscence and recollection of the past, rather than anticipation of the future. If approached constructively, middle age can prepare an individual for a satisfying and productive old age. See also psychological development.

https://www.britannica.com/science/middle-age

Cont aging predisposes-


During normal aging, there are significant alterations in immune functions and tissue responses to stimuli. Aging is associated with a low-grade proinflammatory state and a diminished capacity to mount specific adaptive immune responses resulting in susceptibility to pathology after infectious episodes (Boparai and Korc-Grodzicki, 2011). Immunotherapy (IT) in the treatment of cancer has recently resulted in significant clinical responses and is being increasingly applied (Dougan and Dranoff, 2009). However, as cancer also predominantly occurs within the elderly population (Repetto and Balducci, 2002), these immune alterations that occur with aging potentially also render cancer patients more likely to be susceptible to systemic toxicities after application of systemic IT or in response to infection (Repetto and Balducci, 2002; Brüünsgaard and Pedersen, 2003; Ferrucci et al., 2005; Franceschi, 2007; Chung et al., 2009). Elevated serum levels of proinflammatory cytokines, such as IL-1α, IL-1β, IL-6, and TNF, have been observed with increasing age and are believed to be due to an age-related redox imbalance that activates multiple proinflammatory signaling pathways (Franceschi et al., 2000; Brüünsgaard and Pedersen, 2003; Ferrucci et al., 2005; Chung et al., 2009). The mechanisms underlying the causes and contributors to the age-related proinflammatory state remain unclear. Of concern is that the majority of preclinical studies assessing potential immunotherapeutic regimens use younger mice, which likely fail to replicate human clinical cancer treatment conditions with regard to age. Therefore, understanding the impact of age on IT responses and outcome is critical as significant toxicities can be observed with systemic IT (McInnes et al., 1997; Suntharalingam et al., 2006; Waldmann, 2006; Berger et al., 2009; Attarwala, 2010; Di Giacomo et al., 2010; Weber et al., 2012).
Our studies demonstrate that as opposed to young mice, applying systemic IT in aged mice resulted in rapid and lethal responses due to the induction of a proinflammatory cytokine storm and multiorgan pathology. The elevated cytokine responses occurred with numerous immunostimulatory regimens with proinflammatory cytokine production being mediated by macrophages. TNF was a critical mediator for the increased morbidity, as TNF blockade resulted in partial protection from these lethal systemic toxicities and pathology. Application of TNF blockade also led to successful administration of IT while preserving anti-tumor responses in aged mice. These data indicate that aging results in a heightened predisposition to inflammatory responses by macrophages, which leads to increased susceptibility to multiorgan pathology upon challenge.

How Does TNF Cause Inflammation?

https://www.webmd.com/rheumatoid-arthri ... flammation

It is a very interesting subject now actually as there was much greater mortality from the corona virus in patients older than 60 year and the common cause of death is inflammatory pneumonia as an autoimmune reaction to the novel virus exposure. They also name it a cytokine storm. I have seen that with ICI drugs the storm is greatly elevated IL-6 and its inhibition works without affecting the immune response unlike high dose steroids. If Josh is tested positive for an autoimmune pneumonia, ask for that before discontinuing the treatment.
The case and the full text article is here:
viewtopic.php?f=90&t=1735

Thank you Olga
Will do forward if need be .
I’ve been reading on the cytokine storm as well.
I wonder if the overt symptoms , fever weight loss and or low blood pressure are masked by ICIs ?

Ps Josh will be 40 this year .😊
On another note, his lungs right and left have been worked on but give 98 O2 sats .. to date.
But he has a degree of collateral damage with over 150 tumors having been removed in 2012-2013