Hyperthermia Augments Immunotherapy

 “Science gathers knowledge faster than society gathers wisdom.”

― Isaac Asimov

The author of this quote implies information is equal to knowledge. Information is simply data. Knowledge is acquired through experience and education. Information is a part of knowledge but in no way equates to knowledge. And, neither equates to its application—wisdom.

It is important to recognize the difference between conventional immunotherapy and an integrative, holistic approach to immunotherapy. Conventional immunotherapy is nothing more than modern-day chemotherapy that works within the immune system. It operates under the same philosophy and paradigm as full-dose chemotherapy. The three original pillars of modern-day conventional oncology (surgery, chemotherapy, radiation), particularly chemotherapy, have their birth out of war and the philosophy of war. The conventional immunotherapy approach wants to recreate the wheel—the immune system. In a way, it looks at the immune system as the problem and directly attacks it. Essentially, it is war on two fronts— the cancer and the body. Let’s not forget that the body’s defense is…, you guessed it, the immune system. In contrast to the conventional approach, an integrative, holistic approach to immunotherapy seeks to support, promote, and heal the immune system rather than the obstruction and interference of conventional immunotherapy. There is no need to recreate the wheel. The goal should be to work within the God-created immune defense and support it in its function to protect the body from all enemies, both foreign and domestic. Unfortunately, the immune system is under attack from an unsuspected enemy. The immune system is under attack from both cancer and its least likely attacker—conventional medicine. I have previously discussed immunotherapy in greater detail in a previous post, so check that out in the link above.

Hyperthermia comes to the rescue again. Hyperthermia has been shown to augment both conventional immunotherapy and itself is an effective holistic, integrative immunotherapy.

First, hyperthermia augments conventional immunotherapy. Unfortunately, the documented response rates of conventional immunotherapeutics are batting an approximate < 20% level [1]. That is it. One would think that with all the fanfare and publicity that there was more there there. But sadly, there is not. Besides, that < 20% positive effect does not include cures or remissions. Remember, only God cures, and remission means the cancer is no longer visible. The positive impact of conventional medicine’s immunotherapy approach is mostly confined to statistical creations called disease-free progression, objective response rates, disease free survival, and overall response rates. Disease-free progression means the disease is still present, but the disease did not progress for a determined period of the study. Unfortunately, most of these study periods don’t amount to years and decades but days and months. Objective and overall response rates definitions are no better. Objective response rate means that some positive benefit is seen. What kind of response? And for what time? Is a positive benefit of fifteen or thirty percent an objective response? The same applies to the overall response rate—overall, some response is seen. These research phrases are bountiful in language but clearly amount to nothing more than statistical peanuts in the significant positive impact for people with cancer.

Here are some statistics that document the conventional immunotherapy approach as lackluster. The immune checkpoint inhibitors are the most well-known and published conventional immunotherapeutics on the market. Think of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) as the first team of conventional immunotherapy. You may know these by their well-marketed drug names of keytruda, opdivo, and others. Program cell death-Ligand 1 (PD-L1) interacts with PD-1 on T-cells to decrease activation of T-cells and decrease their attack of cancer cells. The use of immune checkpoint inhibitors in the treatment of melanoma [2] and lung cancer [3] [4] yields a 40-45% objective response rate. The use of the same immune checkpoint inhibitor therapies in the treatment of bladder cancer yields only a 13–24% improvement in overall response rate [5]. That is not an overall 40-50% or 13-24% improvement, but an improvement in response rate above current conventional treatment standards that are failing. That is like saying, instead of an F-, the result is straight out F. Sorry, it still is a failing grade. One of the more difficult to treat cancers is triple-negative breast cancer. A recent study chose to highlight the 19% response rate of immune checkpoint inhibitors as ‘moderate’ for the treatment of triple-negative breast cancer [6] [7]. Hmmm. Moderate clearly has been redefined for the purpose of that study. Some of the best response rates occur in Hodgkin’s lymphoma treatment, where an 87% objective response rate is seen. As good as that number seems, the percentage precipitously dropped to 17% when the authors looked at the complete response rate [8]. I haven’t even mentioned the long list of side effects and the cost-benefit ratio that is upside down that accompanies the documented low yield response rates [9]. A recent 2019 article published in the journal Nutrients put it bluntly: “The consequence is usually about 50% irreversible in immune-related endocrine toxicities” [10]. Ouch! It is readily apparent that much of the research published today amounts to nothing more than a statistical word puzzle.

One of the more positive headlines for conventional immunotherapy is in the treatment of HER-2 positive breast cancer. HER-2 expression is associated with ER-/PR-, invasion, younger age at diagnosis, higher grade, increased tumor size, increase early spread to the lymph noes, increased aggressiveness and recurrence of breast cancer. Another prominent class of conventional immunotherapy is the monoclonal antibodies. I will give credit where credit is, in fact, due. The drug Herceptin (trastuzumab), a monoclonal antibody, has significantly benefited patients with HER-2 positive breast cancer. A 2014 study found that Herceptin + conventional chemotherapy increased the overall 10-year survival by 37% and disease-free survival by 40% in early-stage HER-2 positive breast cancer [11]. That 37% and 40% is an improvement above the baseline of conventional chemotherapy only; it is not an overall increase. And it was in early-stage cancer. What about advanced-stage cancer?

I know it seems like I am vilifying conventional immunotherapy. I am not. We do use conventional immunotherapeutics from time to time. The problem is that they are marketed as modern-day saviors, yet they clearly are not. The problem is the low bar medicine sets for our results and, most importantly, for patients. We need to do better. We must do better. But to do this, medicine will have to undergo a think shift—a paradigm shift in thinking.

How about some good news about conventional immunotherapy? Hyperthermia augments conventional immunotherapy:

  • Immune checkpoint inhibitor therapy [12] [13]
  • Monoclonal antibody therapy [14]
  • Conventional dendritic cell vaccines [15] [16]

Hyperthermia works synergistically with conventional immunotherapeutic drugs. I will dive into some of the more specific, detailed immune effects of hyperthermia in a future post.

Contrary to false perception perpetuated by conventional medicine and their media allies, one does not throw research to the side to use holistic, natural therapies. Quite the opposite is true. An analysis of the strength and a large amount of research available requires a move to a more natural approach. One simply has to look, read, and have an open mind. Unfortunately, all three are a rarity today and biases and unseen agendas reign. Research highlights the fact that hyperthermia augments and synergistically works with holistic immunotherapies:

And then there is the in-between immunotherapy—what is called integrative immunotherapy. These therapies may not be exactly holistic, yet they follow a more holistic strategy in treatment approach. These approaches definitely do not follow the conventional mindset or approach to immunotherapy.

Medicine is about science—an honest read, debate, and application of scientific information. It also is about independent and creative thinking; at least it should be. It is this process that provides the wisdom which supersedes the pure accumulation of information. A disturbing trend today is a move away from debate in science to the theology of science. What is seen today is more of the worship of science—something called scientism. Anyone that dares to read any text and literature counter to the approved theological text, or speak out with a difference in scientific opinion, or draw an independent conclusion is deemed a heretic cast to the 9th level of hell only to be redeemed at the alter of scientism. When there is no knowledge through the application of information, there is no wisdom.

Coinciding with this theological worship of science is the rise of corporate science. Corporate science is an exclusive circle of big corporations, government, and big money. Today, the accumulation of information and profits drives corporate science. We have today the rapid accumulation of vast amounts of information without the wisdom for the application of the information. That is not knowledge; that is a dark road for all involved, most particularly patients. Hmmm. History has seen and tried this before.

[1] Bratman SV, Yang  SYC, Iafolla MAJ. et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer. 2020;1:873–881. https://doi.org/10.1038/s43018-020-0096-5

[2] Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 2015;373:23–34.

[3] Garon, E. B. et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N. Engl. J. Med. 2015;372:2018–2028.

[4] Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N. Engl. J. Med. 2015;373:1627–1639.

[5] Cheng, W., Fu, D., Xu, F. & Zhang, Z. Unwrapping the genomic characteristics of urothelial bladder cancer and successes with immune checkpoint blockade therapy. Oncogenesis. 2018; 7,2.

[6] Polk, A., Svane, I. -M., Andersson, M. & Nielsen, D. Checkpoint inhibitors in breast cancer: Current status. Cancer Treat. Rev. 2013;63:122–134.

[7] Darvin, P., Toor, S.M., Sasidharan Nair, V. et al. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50:1–11. https://doi.org/10.1038/s12276-018-0191-1

[8] Ansell, S. M. et al. PD-1 Blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N. Engl. J. Med. 2014;372:311–319.

[9] Feng Y. et al. Exposure–response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin. Can. Res. 2013:19,3977.

[10] Yang YSH, Li ZL, Shih YJ, et al. Herbal Medicines Attenuate PD-L1 Expression to Induce Anti-Proliferation in Obesity-Related Cancers. Nutrients. 2019;11(12):2979. Published 2019 Dec 5. doi:10.3390/nu11122979

[11] Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. Nov 2014;32(33):3744-52. doi: 10.1200/JCO.2014.55.5730.

[12] Takeda T, Kubota Y, Takeda T, Nakano Y, Nogami Y, Honjoh I, Takeda H, Yokoyama Y, Yamamoto H. [Enhancing Antitumor Effects Using Hyperthermia(Including Immune Checkpoint Inhibitor)]. Gan To Kagaku Ryoho. 2018 Oct;45(10):1479-1481. Japanese. PMID: 30382051.

[13] Li Z, Deng J, Sun J, Ma Y. Hyperthermia Targeting the Tumor Microenvironment Facilitates Immune Checkpoint Inhibitors. Front Immunol. Nov 2020.https://doi.org/10.3389/fimmu.2020.595207

[14] Hauck ML, Dewhirst MW, Bigner DD, Zalutsky MR. Local hyperthermia improves uptake of a chimeric monoclonal antibody in a subcutaneous xenograft model. Clin Cancer Res. 1997 Jan;3(1):63-70.

[15] Wang XY, Kazim L, Repasky EA, Subjeck JR. Characterization of heat shock protein 110 and glucose-regulated protein 170 as cancer vaccines and the effect of fever-range hyperthermia on vaccine activity. J Immunol. Jan 2001;166(1):490-7. doi: 10.4049/jimmunol.166.1.490.

[16] Calderwood SK, Gong J, Stevenson MA, Murshid A. Cellular and molecular chaperone fusion vaccines: targeting resistant cancer cell populations. Int J Hyperthermia. Aug 2013;29(5):376-9. doi: 10.3109/02656736.2013.792126.

[17] Mukhopadhaya A, Mendecki J, Dong X, Liu L, Kalnicki S, Gary M, Algiers A, Gujarati C. Localized Hyperthermia Combined with Intratumoral Dendritic Cells Induces Systemic Antitumor Immunity. Cancer Res. Aug 2007;(67)16:7798-7806; DOI: 10.1158/0008-5472.CAN-07-0203

[18] Ostberg JR, Kabingu E, Repasky EA. Thermal regulation of dendritic cell activation and migration from skin explants. Int J Hyperthermia. Sep-Oct 2003;19(5):520-33. doi: 10.1080/02656730310001607986.

[19] Terunuma H, Den X, Toki A, Yoshimura A, Nishino N, Takano Y, Nieda M, Sasanuma JI, Teranishi Y, Watanabe K. Effects of Hyperthermia on the Host Immune System : From NK Cell-based Science to Clinical Application. Therm Med. 2012;28(1):1-9.

[20] Terunuma H. et al. (2016) Combining Hyperthermia and Immunotherapy: NK Therapy and Hyperthermia. In: Kokura S., Yoshikawa T., Ohnishi T. (eds) Hyperthermic Oncology from Bench to Bedside. Springer, Singapore. https://doi.org/10.1007/978-981-10-0719-4_29

[21] Ou J, Zhu X, Chen P, Du Y, Lu Y, Peng X, Bao S, Wang J, Zhang X, Zhang T, Pang CLK. A randomized phase II trial of best supportive care with or without hyperthermia and vitamin C for heavily pretreated, advanced, refractory non-small-cell lung cancer. J Adv Res. 2020 Mar 17;24:175-182. doi: 10.1016/j.jare.2020.03.004.

[22] Ou J, Zhu X, Lu Y, Zhao C, Zhang H, Wang X, Gui X, Wang J, Zhang X, Zhang T, Pang CLK. The safety and pharmacokinetics of high dose intravenous ascorbic acid synergy with modulated electrohyperthermia in Chinese patients with stage III-IV non-small cell lung cancer. Eur J Pharm Sci. 2017 Nov 15;109:412-418. doi: 10.1016/j.ejps.2017.08.011.

[23] Quintana C, Cabrera J, Perdomo J, Estévez F, Loro JF, Reiter RJ, Quintana J. Melatonin enhances hyperthermia-induced apoptotic cell death in human leukemia cells. J Pineal Res. 2016 Oct;61(3):381-95. doi: 10.1111/jpi.12356.

[24] Schirrmacher V, Lorenzen D, Van Gool SW and Stuecker W. A New Strategy of Cancer Immunotherapy Combining Hyperthermia/Oncolytic Virus Pretreatment with Specific Autologous Anti-Tumor Vaccination – A Review. Austin Oncol Case Rep. 2017;2(1):1-8.

[25] Song J, Zhang F, Ji J, Chen M, Li Q, Weng Q, Gu S, Kogut MJ, Yang X. Orthotopic hepatocellular carcinoma: molecular imaging-monitored intratumoral hyperthermia-enhanced direct oncolytic virotherapy. Int J Hyperthermia. 2019;36(1):344-350. doi: 10.1080/02656736.2019.1569731.

[26] Eisenberg DP, Carpenter SG, Adusumilli PS, Chan MK, Hendershott KJ, Yu Z, Fong Y. Hyperthermia potentiates oncolytic herpes viral killing of pancreatic cancer through a heat shock protein pathway. Surgery. 2010 Aug;148(2):325-34. doi: 10.1016/j.surg.2010.05.005.

[27] Hu F, Hu XH, Yu P, Zhang JX, Lou GG, Liu HL, Wu B, Zhao RH, Xia HQ, Wang Y, Chen J, Ben Y, Chen SY. [Abscopal effect on metastatic tumor induced by oncolytic virus of H101 combining with local heating]. Ai Zheng. 2006 Aug;25(8):919-24.

[28] Issels RD, Lindner LH, von Bergwelt-Baildon M, Lang P, Rischpler C et al. Systemic antitumor effect by regional hyperthermia combined with low-dose chemotherapy and immunologic correlates in an adolescent patient with rhabdomyosarcoma – a case report, International Journal of Hyperthermia. 2020;37:1:55-65, DOI: 10.1080/02656736.2019.1709666

[29] Sumiyoshi K, Strebel FR, Rowe RW, Bull JM. The effect of whole-body hyperthermia combined with ‘metronomic’ chemotherapy on rat mammary adenocarcinoma metastases. Int J Hyperthermia. 2003 Mar-Apr;19(2):103-18. doi: 10.1080/0265673021000017091.

[30] Franchi F, Grassi P, Ferro D, Pigliucci G, De Chicchis M, Castigliani G, Pastore C, Seminara P. Antiangiogenic metronomic chemotherapy and hyperthermia in the palliation of advanced cancer. European Journal of Cancer Care. 2007;16: 258–262.

[31] Geehan DM, Fabian DF, Lefor AT. Immunotherapy and whole-body hyperthermia as combined modality treatment of a subcutaneous murine sarcoma. J Surg Oncol. 1993 Jul;53(3):180-3. doi: 10.1002/jso.2930530310.

[32] Geehan DM, Fabian DF, Lefor AT. Combined local hyperthermia and immunotherapy treatment of an experimental subcutaneous murine melanoma. Journal of Surgical Oncology. 1995 May;59(1):35-39. DOI: 10.1002/jso.2930590110.

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