I came across this treatment route a few years ago and I had and still have a very good feeling about it. So, I thought it may help to increase the awareness if I share here a bit about it:
CRM197 (cross-reacting material 197) is a non-toxic form of diphtheria toxin. Diphtheria is an infection caused by the bacterium Corynebacterium diphtheriae (Ref.). While diphtheria toxin is very toxic, its nontoxic version CRM197 is used as a carrier protein in a number of FDA approved conjugate vaccines. The lack of toxicity is due to the placement of a glutamic acid in place of glycine at position 52.
The story of diphtheria toxin in cancer research goes back to 70’s when an innovative Italian doctor, Silvio Buzzi (3 August 1930 – 14 July 2009), started documenting his research in this space (Ref.). Latter, during 80’s he started to test the non toxic version of diphtheria toxin CRM197 in cancer patients will all kind of various solid tumors. First, he investigated the immunity of the patients to the CRM197 and found out that 70% of the patients had anti-diphtheria immunity which means that in this cases higher dose of the vaccine would be required (Ref.). Next, he applied the vaccine in humans on compassionate basis. The published outcome of that was indicating an overall response rate of 48%, including complete-, partial-response and stable disease (Ref.). In the following decades Dr. Silvio Buzzi continued to administrate CRM197 either as intra peritoneal injection or intravenously to cancer patients with positive outcomes (Ref.). During all this time he also found out by chance that cancer patients treated with CRM197 who also had atherosclerotic stenoses, besides tumor reductions have also seen serious reduction of the atherosclerotic stenosis. (Ref.) In contrast to all these positive results, a recent clinical trial taking place in Italy and including a limited number of mainly melanoma patients was unable to obtain response (CRM197 was administered subcutaneously in the abdominal wall). (Ref.)
Dr. Silvio Buzzi has gain very limited support from the Italian responsible organisations. As a result, he started collaborating with Japanese researcher, who in turn were well supported by the Japanese Ministry of Health. (Ref.)
In this context, Prof. Eisuke Mekada et al. in Japan, have found that CRM197 has important anti-cancer effects and may also reverse the resistance of the ovarian cancer cells to paclitaxel. (Ref.1, Ref.2). This effect was due to the major anti cancer action of CRM197 which seems to be related to its capability to bind to and inhibit HB-EGF (Ref.) HB-EGF, which will be discussed in more details in the “Mechanism” section is a protein over expressed in multiple cancers (and ascites) such as
- ovarian (Ref.),
- adrenal (Ref.),
- triple-negative breast cancer (Ref.) and breast cancer in general (Ref.1, Ref.2),
- neuroblastoma (Ref.),
- gastric cancer (Ref.)
- oral cancer (Ref.)
A clinical trial involving CRM197 seems to be running in Japan with encouraging results (Ref.).
In order to create awareness of and continue the great work of Dr. Silvio Buzzi, Buzzi family and others supporters have cratered Silvio Buzzi Foundation: http://www.crm197.it/ My experience in communication with the Foundation was great. I rarely met such a kind and supporting people.
One challenge with CRM197 is that its price is in the range of a few to several k euro depending on the patient wight (prices at chemical suppliers) and supplier. This is why Dr. Silvio Buzzi could not treat large number of patients. The other challenge is the immunity of the patients. As discussed above, a good part of the patients have immunity to CRM197 which means that CRM197 may be destroyed by the immune system before reaching the tumor in which case higher doses have been used in the trials. In this case, the best approach if available would be to administrate the vaccine close to the tumor site.
Case Report on Humans:
1982: Diphtheria toxin treatment of human advanced cancer. http://www.ncbi.nlm.nih.gov/pubmed/6279291
Purified diphtheria toxin was administered i.v. to 50 patients with advanced solid tumors. The doses of toxin varied according to the different immunological status of the patients against diphtheria. The prominent toxic effects of the treatment were transient peripheral neuropathy observed in two nonimmune patients and fever (37-41 degrees) which occurred in all immune patients with cell-mediated hypersensitivity to toxin. A partial response to lasting from 2 to 4 weeks was achieved in three of 13 nonimmune patients and in one of three nonimmune patients with cell-mediated hypersensitivity. Of 21 immune patients, nine had partial response lasting from 4 to 12 weeks. Of 13 immune patients with cell-mediated hypersensitivity, six had partial and five complete response lasting from 2 to 12 and from 1 to 25+ months, respectively. The overall response rate was 48%. The results suggest that diphtheria toxin may have a role in cancer immunotherapy.
2004: CRM197 (nontoxic diphtheria toxin): effects on advanced cancer patients. http://www.ncbi.nlm.nih.gov/pubmed/15168087
PURPOSE: Many years ago, diphtheria toxin (DT) showed antitumor activity in mice and in humans, but it was unclear whether this depended on the toxicity of the molecule only or on its strong inflammatory-immunological property as well. To deal with this open question, we planned to treat a group of cancer patients with cross-reacting material 197 (CRM197). CRM197 is a nontoxic mutant of DT that shares the immunological properties of the native molecule and its ability to bind to heparin-binding epidermal growth factor (HB-EGF), the specific cell-membrane receptor for DT that is often overexpressed in cancer.
METHODS: 25 outpatients with various advanced tumors who were refractory to standard therapies (23 subjects) or had refused, in whole or in part, conventional therapies (2 subjects) were treated with CRM197 injected subcutaneously in the abdominal wall, on alternate days, for 6 days. Three different dosages (1.7, 2.6, or 3.5 mg/day) were used according to the patient’s degree of immunological reactivity to DT/CRM197 (none, moderate, or high).
RESULTS: After the first administration of CRM197, a significant increase in the number of circulating neutrophils and in the serum level of TNF-alpha was detected. Toxicities were minimal. Only patients with delayed-type hypersensitivity to DT/CRM197 had irritating skin reactions in the injection sites and a flu-like syndrome with fever. Pharmacokinetics showed a mean peak concentration (12.7 ng/ml) 12 h after the first injection and a mean half-life of 18.1 h. There were two complete and one partial responses (metastatic breast carcinoma, neuroblastoma, and metastatic breast carcinoma) lasting 4, 45+, and 15 months, respectively. Six cases of stable disease, lasting from 1 to 15 months, were also recorded.
CONCLUSIONS: CRM197 injected subcutaneously elicited an inflammatory-immunological reaction, caused tolerable toxicities, was absorbed to a good extent into the circulatory system, and exerted some degree of biological antitumor activity. A possible role of neutrophils and TNF-alpha in the mode of action of the molecule is hypothesized.
Heparin-binding EGF (epidermal growth factor)-like growth factor (HB-EGF) is an EGFR (epidermal growth factor receptor) ligand that plays a pivotal role in tumor growth and clinical outcomes in patients (Ref.). HB-EGF gene expression in cancerous tissues and HB-EGF protein levels were shown to be significantly elevated in patients’ ascites. In addition, HB-EGF tumor formation by human ovarian cancer cell lines was enhanced by exogenous expression of HB-EGF and completly blocked by CRM197. This is because CRM197 possess a binding site for HB-EGF and inhibits HB-EGF binding to and as a result activation of EGFR (which is also well known to be highly expressed in many types of tumors). As a results CRM197 is known as a HB-EGF inhibitor. (Ref.)
Indeed, HB-EGF gene expression is significantly elevated in human ovarian cancer, and it was demonstrated that HB-EGF plays key roles in the acquisition of malignant phenotypes, such as cell survival in peritoneal fluid, cell adhesion on extracellular matrices, invasion, angiogenesis, tumorigenicity, and chemoresistance in ovarian cancer. (Ref.) Misexpression of HB-EGF is linked to tumor formation and cancer including hepatocellular, pancreatic, gastric, breast, colon and melanoma, gliomas and glioblastomas. (Ref.)
Note that cancer cells with elevated expression of HB-EGF are also resistant to chemo therapies such as paclitaxel. (Ref.)
The relevance of HB-EGF modulation goes beyond cancer, e.g. hydrocephalus (Ref.), chronic kidney disease (Ref., Ref.2). HB-EGF plays important roles in several biological and pathological processes, such as wound healing, blastocyst implantation, atherosclerosis, and heart development (Ref.).
Administration Protocol and Dose:
Check the options with Silvio Buzzi Foundation and the enclosed reference: http://www.crm197.it/
Check the options with Silvio Buzzi Foundation: http://www.crm197.it/
Possible normal side effects: a red halo, fever, itching. Usually, only a red halo at the injection site.
Not reported in the clinical trials but I guess at high dose there may be a negative impact related to heart?: HB-EGF signaling through ErbB2 is essential for the maintenance of homeostasis in the adult heart, whereas HB-EGF signaling through EGFR is required during cardiac valve development. (Ref.)
A potent anti-HB-EGF monoclonal antibody inhibits cancer cell proliferation and multiple angiogenic activities of HB-EGF. http://www.ncbi.nlm.nih.gov/pubmed/23251664
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the epidermal growth factor family and has a variety of physiological and pathological functions. Modulation of HB-EGF activity might have a therapeutic potential in the oncology area. We explored the therapeutic possibilities by characterizing the in vitro biological activity of anti-HB-EGF monoclonal antibody Y-142. EGF receptor (EGFR) ligand and species specificities of Y-142 were tested. Neutralizing activities of Y-142 against HB-EGF were evaluated in EGFR and ERBB4 signaling. Biological activities of Y-142 were assessed in cancer cell proliferation and angiogenesis assays and compared with the anti-EGFR antibody cetuximab, the HB-EGF inhibitor CRM197, and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab. The binding epitope was determined with alanine scanning. Y-142 recognized HB-EGF as well as the EGFR ligand amphiregulin, and bound specifically to human HB-EGF, but not to rodent HB-EGF. In addition, Y-142 neutralized HB-EGF-induced phosphorylation of EGFR and ERBB4, and blocked their downstream ERK1/2 and AKT signaling. We also found that Y-142 inhibited HB-EGF-induced cancer cell proliferation, endothelial cell proliferation, tube formation, and VEGF production more effectively than cetuximab and CRM197 and that Y-142 was superior to bevacizumab in the inhibition of HB-EGF-induced tube formation. Six amino acids in the EGF-like domain were identified as the Y-142 binding epitope. Among the six amino acids, the combination of F115 and Y123 determined the amphiregulin cross-reactivity and that F115 accounted for the species selectivity. Furthermore, it was suggested that the potent neutralizing activity of Y-142 was derived from its recognition of R142 and Y123 and its high affinity to HB-EGF. Y-142 has a potent HB-EGF neutralizing activity that modulates multiple biological activities of HB-EGF including cancer cell proliferation and angiogenic activities. Y-142 may have a potential to be developed into a therapeutic agent for the treatment of HB-EGF-dependent cancers.
Identification of the cancer cell proliferation and survival functions of proHB-EGF by using an anti-HB-EGF antibody. http://www.ncbi.nlm.nih.gov/pubmed/23349913
PURPOSE: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the epidermal growth factor family. The membrane-bound proHB-EGF is known to be a precursor of the soluble form of HB-EGF (sHB-EGF), which promotes cell proliferation and survival. While the functions of sHB-EGF have been extensively studied, it is not yet fully understood if proHB-EGF is also involved in cellular signaling events. In this study, we utilized the anti-HB-EGF monoclonal antibodies Y-142 and Y-073, which have differential specificities toward proHB-EGF, in order to elucidate proHB-EGF functions in cancer cells.
EXPERIMENTAL DESIGN: The biological activities of proHB-EGF were assessed in cell proliferation, caspase activation, and juxtacrine activity assays by using a 3D spheroid culture of NUGC-3 cells.
RESULTS: Y-142 and Y-073 exhibited similar binding and neutralizing activities for sHB-EGF. However, only Y-142 bound to proHB-EGF. We could detect the function of endogenously expressed proHB-EGF in a 3D spheroid culture. Blocking proHB-EGF with Y-142 reduced spheroid formation, suppressed cell proliferation, and increased caspase activation in the 3D spheroid culture of NUGC-3 cells.
CONCLUSIONS: Our results show that proHB-EGF acts as a cell proliferation and cell survival factor in cancer cells. The results suggest that proHB-EGF may play an important role in tumor progression.
Cancer Immunity after Treatment of Ehrlich Tumor with Diphtheria Toxin http://cancerres.aacrjournals.org/content/canres/34/12/3481.full.pdf
Synergistic anti-tumor effect of paclitaxel with CRM197, an inhibitor of HB-EGF, in ovarian cancer http://onlinelibrary.wiley.com/doi/10.1002/ijc.24031/pdf
Heparin-binding EGF-like growth factor (HB-EGF) plays a pivotal role in tumor growth and clinical outcomes in patients with ovarian cancer, leading to the validation of HB-EGF as a target for ovarian cancer therapy. In this study, we investigated the antitumor effects of paclitaxel, as an anti-cancer agent, and CRM197, as a specific inhibitor off HB-EGF, in ovarian cancer. Paclitaxel induced transient ERK activation and sustained activation of JNK and p38 MAPK through the ectodomain shedding of HB-EGF in SKOV3 cells. In addition, the overexpression of HB-EGF in paclitaxel-treated SKOV3 cells resulted in modulation of paclitaxelevoked MAPK signaling, including marked activation of ERK and Akt, and minimized activation of JNK and p38 MAPK, indicating that HB-EGF is involved in drug sensitivity through the balance of anti-apoptotic and pro-apoptotic signals induced by paclitaxel. The combination of paclitaxel with CRM197 had an inhibitory effect on cell proliferation and enhanced apoptosis via the inhibition of ERK and Akt activation and the stimulation of p38 and JNK activation. More prominently, the administration of paclitaxel with CRM197 resulted in synergistic anti-tumor effects in SKOV3 cells and in SKOV3 cells overexpressing HB-EGF in xenografted mice. Accordingly, inhibitory agents against HB-EGF, such as CRM197, represent possible chemotherapeutic and chemosensitizing agents for ovarian cancer.
Synergistic anti-tumor effect of paclitaxel with CRM197, an inhibitor of HB-EGF, in ovarian cancer. http://www.ncbi.nlm.nih.gov/pubmed/19048624
Heparin-binding EGF-like growth factor (HB-EGF) plays a pivotal role in tumor growth and clinical outcomes in patients with ovarian cancer, leading to the validation of HB-EGF as a target for ovarian cancer therapy. In this study, we investigated the anti-tumor effects of paclitaxel, as an anti-cancer agent, and CRM197, as a specific inhibitor off HB-EGF, in ovarian cancer. Paclitaxel induced transient ERK activation and sustained activation of JNK and p38 MAPK through the ectodomain shedding of HB-EGF in SKOV3 cells. In addition, the overexpression of HB-EGF in paclitaxel-treated SKOV3 cells resulted in modulation of paclitaxel-evoked MAPK signaling, including marked activation of ERK and Akt, and minimized activation of JNK and p38 MAPK, indicating that HB-EGF is involved in drug sensitivity through the balance of anti-apoptotic and pro-apoptotic signals induced by paclitaxel. The combination of paclitaxel with CRM197 had an inhibitory effect on cell proliferation and enhanced apoptosis via the inhibition of ERK and Akt activation and the stimulation of p38 and JNK activation. More prominently, the administration of paclitaxel with CRM197 resulted in synergistic anti-tumor effects in SKOV3 cells and in SKOV3 cells overexpressing HB-EGF in xenografted mice. Accordingly, inhibitory agents against HB-EGF, such as CRM197, represent possible chemotherapeutic and chemosensitizing agents for ovarian cancer.
Anti-tumor Effect of Intravenous Administration of CRM197 for Triple-negative Breast Cancer Therapy. http://www.ncbi.nlm.nih.gov/pubmed/27354636
BACKGROUND/AIM: Heparin-binding epidermal growth factor-like growth factor (HB-EGF), which belongs to the epidermal growth factor family, is a rational therapeutic target for triple-negative breast cancer (TNBC). This study aimed to assess the anti-tumor efficacy of intravenous (i.v.) HB-EGF-specific inhibitor (CRM197) for TNBC.
MATERIALS AND METHODS: NOD/SCID mice were subcutaneously injected withTNBC cells, MDA-MB-231, and, then, treated with i.v. CRM197 in either dose- or frequency-dependent manners, using an advanced cancer model and an adjuvant therapy model. Tumor volume and mouse body weight were calculated weekly. Statistical significance was assessed by the Mann-Whitney U-test.
RESULTS: Mice that received i.v. CRM197 showed a significant anti-tumor effect in dose- and frequency-dependent manners in both models. However, their body weight did not differ significantly among groups.
CONCLUSION: These results suggest that i.v. CRM197 is an effective treatment for TNBC.
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