Dr. Weeks’ Comment: Granted it is best never to have to fight cancer, but if you do get cancer, now is a far better time than anytime over the past 50 years. Why? Because the standard of care for cancer treatment, chemotherapy and radiation therapy – both of which have always caused more harm than benefit – are on the way out. did you know that the benefit of chemotherapy in an adult was carefully studied and published in the Journal of Clinical Oncology in 2004 . The benefit was only 2.1% ! Think about it. 2 people out of 100 benefit. Yikes!
The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies.
The debate on the funding and availability of cytotoxic drugs raises questions about the contribution of curative or adjuvant cytotoxic chemotherapy to survival in adult cancer patients.
The overall contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults was estimated to be 2.3% in Australia and 2.1% in the USA.
As the 5-year relative survival rate for cancer in Australia is now over 60%, it is clear that cytotoxic chemotherapy only makes a minor contribution to cancer survival. To justify the continued funding and availability of drugs used in cytotoxic chemotherapy, a rigorous evaluation of the cost-effectiveness and impact on quality of life is urgently required.
Now, I have lectured extensively on this fact and taught audiences around the world to chant “Friends don’t let friends get chemotherapy”. Why is chemotherapy so bad – watch at least the first 5 minutes of this lecture.
But the good news is that, as I have predicted, the toxic standard of care is being replaced by 2 safe and effective remedies: 1) anti-inflammatory agents (foods are safest) and 2) immune-enhancing agents (once-immunology)
Read below about a breakthrough which – though not proven yet – is promising.
Inhibition of type I IFN prevents autoimmune toxicity while preserving antitumor efficacy of combined cancer vaccine and adoptive cell therapy.
Cancer immunotherapy—includings immune checkpoint inhibition (ICI), adoptive cell therapy (ACT), and cancer vaccines—is revolutionizing cancer treatment. Although ACT is successful in some hematological malignancies, it has limited effects in solid tumors. Therapeutic cancer vaccines have not achieved much clinical success so far. Additionally, immunotherapy can be accompanied by widespread and potentially fatal autoimmune toxicities. Intense investigation is under way to enhance the efficacy of immunotherapy and to minimize autoimmune toxicity.
Walsh and colleagues combined tumor antigen–specific T cell ACT with a viral cancer vaccine to efficiently treat established melanoma in mice, suggesting that the combination of vaccination and ACT, but not individual therapy, could be effective in solid tumors. As expected, their combination therapy induced autoimmunity. The location of the autoimmune response was dependent on where the tumor antigen, often a self-antigen, is expressed, confirming that T cell recognition of self-antigen in tumor leads to autoimmunity. Importantly, they discovered that type I interferon (IFN) induced by the cancer vaccine was coupled to the autoimmune response. Blockade of type I IFN signaling, either by administration of neutralizing antibody or by genetic ablation of type I IFN signaling in the mice, prevented autoimmunity. Moreover, utilization of an alternative viral vector with reduced type I IFN induction also inhibited the autoimmune response without compromising antitumor efficacy. Mechanistically, type I IFN increased major histocompatibility complex I (MHC I) expression on normal tissues, which permitted the autoimmune response. In contrast, their combination therapy induced MHC I expression on tumor cells independent of type I IFN.
This study identifies a potential target to reduce cancer immunotherapy–associated autoimmune toxicity in animal models of combined ACT and cancer vaccine therapy. Several key questions remain. Does the pathway apply to other modes of cancer immunotherapy with significant autoimmune toxicity, such as ICI therapy? More importantly, whether this insight can be translated into human clinical application awaits further investigation. In addition, type I IFN is also known to enhance memory T cell differentiation. Thus, it remains to be determined whether type I IFN blockade may inadvertently increase cancer relapse in the long run.
J Clin Invest. 2018 Dec 18. pii: 121004. doi: 10.1172/JCI121004. [Epub ahead of print]
Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity.Walsh SR1, Bastin D1, Chen L1, Nguyen A1, Storbeck CJ2,3, Lefebvre C4, Stojdl D3,4, Bramson JL1, Bell JC2,3, Wan Y1.
Despite its success in treating melanoma and hematological malignancies, adoptive cell therapy (ACT) has had only limited effects in solid tumors. This is due in part to a lack of specific antigen targets, poor trafficking and infiltration, and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVVs) to drive expansion and tumor infiltration of transferred antigen-specific T cells and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequences when the antigen targeted was a self-protein. However, modulation of IFN-α/-β signaling, either by functional blockade or rational selection of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFN-α/-β in facilitating autoimmune toxicity during cancer immunotherapy and presents a safe and powerful combinatorial regimen with immediate translational applications.