Bacterial Infections and Cancer Remissions

Epistemic status: pretty confident but only making weak claims

In previous posts I’ve talked about how progress on cancer treatment has slowed and how recent targeted chemotherapy drugs are mostly ineffective, and floated some heuristics as to how we might approach cancer research better.  In this and subsequent posts I’ll look at some examples of therapies and research directions that I think are promising. Mostly these aren’t of the form “this is a cure for cancer, go out and take it right now” so much as they are “there might be a cure for cancer around this vicinity, it needs further research, and it seems underappreciated.”  I don’t claim to have an exhaustive list, but I do think I have enough examples to convince a reader that there’s a lot more interesting stuff out there than the conventional “cancer is hard because the low-hanging fruit is gone” story would imply.

In this post, I want to talk about the evidence that bacterial infections sometimes cause complete remissions in cancers.

Antitumor Immunity

Since the 1980s, the scientific consensus has converged on the view that the immune system destroys cancerous cells as they arise. A clinical case of cancer is simply one in which the body fails to fight off the tumor before it becomes large enough to be measurable or cause symptoms.

The current model of antitumor immunity works as follows:

Here’s how antitumor immunity is currently believed[1] to work:

  • dendritic cells sample antigens from the tumor
  • dendritic cells receive a signal to mature and differentiate
  • these activated dendritic cells generate T-cell responses in the lymphatic tissues
  • cytotoxic T cells enter the tumor to perform their function

So activating either dendritic cells or T-cells could result in a stronger immune response to cancer. This is the theory behind many experimental immunotherapies, including cancer vaccines and CAR T-cell immunotherapy.[2]

Spontaneous Remission and Regression

Sometimes cancer regresses or disappears by itself, without treatment; very frequently these cases follow a feverish infection.  There have been many anecdotal and historical accounts of such “miraculous” recoveries, including the story of St. Peregrine.[3]

A review [4] of case studies found 237 cases of spontaneous regression in 1900-1965, and 504 cases from 1966-1987.  These occurred in many kinds of solid and hematological cancers. The most common kinds were kidney, neuroblastoma, malignant melanoma, choriocarcinoma, and bladder.  These are not the commonest cancers; lung, colon, and breast cancer were underrepresented among spontaneous regressions.  Another review [5] observed that “the prevalent view regarding the mechanism for spontaneous regression is the involvement of immunological factors in the host,” noting that regressing tumors have been observed to have elevated cytokine counts or elevated levels of cytotoxic lymphocytes.  A 1976 survey [8] concluded, “Spontaneous remission of acute leukemia is associated with bacterial infection and is of short duration, weeks to months. Spontaneous regression of lymphoma or plasma cell dyscrasia is often of substantial duration, months or years, and frequently is associated with viral infections.” Another review article [10] confirms the relationship between bacterial infection and spontaneous remission in leukemia: “In 1950, Shear reported that brief remissions in children with untreated leukemia were observed in about 10% of the patients. Three quarters of these remissions were preceded by an episode of acute infection.”

A case study [6] from 1976 of a patient with malignant melanoma who refused treatment observed a spontaneous remission; there was an inflammatory reaction with lymphocytic infiltrate and increased lymphocyte cytotoxicity over the time course of regression, consistent with an immunological cause.

A case study [7] of acute myeloblastic leukemia found a spontaneous remission; the remission occurred after a severe febrile pneumonia, which was treated with leukocyte transfusions.

A case study [9] of two patients with acute myeloblastic leukemia observed that both had spontaneous remissions after infection and blood transfusions.

A case study [11] of a patient with acute myeloid leukemia observed a spontaneous remission after a severe streptococcal infection.

A case study [12] of a patient with hepatocellular carcinoma observed a spontaneous remission following massive gastrointestinal hemorrhage, shock, and blood transfusion.

A case series [13] of 52 patients observed that postoperative empyema (collection of pus in the body) after pneumoectomy increases five-year survival in lung cancer from 18% to 50%.

Finally, it is a traditional observation that a history of infectious disease anticorrelates with cancer risk.  A literature review [14] found that cancer patients are less likely than healthy patients to have a history of febrile infections.  “Individuals who had never experienced a febrile infectious disease were 2.5–46.2 times more likely to have developed cancer than those who had had febrile infections.”

This body of evidence suggests that the immune response to infectious disease has an antitumor effect.

Coley Toxins

In 1891, surgeon William Coley treated a patient with a sarcoma by injecting Streptococcus pyogenes culture into the tumor, and caused a complete regression and 8-year remission, after a severe erysipelas infection from which the patient almost died. Heat-killed Streptococci were safer, but didn’t have a tumor-shrinking effect.  Adding heat-killed Serratia marrescens to the mixture made it effective again, and caused 60 out of 210 (29%) terminally ill sarcoma patients to have relapse-free survival of more than 10 years.[10]   By comparison, modern 5-year survival rates [23] for soft-tissue sarcoma are 83% for localized sarcoma, 54% for regional sarcoma, and 16% for sarcoma with distant spread. So Coley’s patients may have had better or comparable results to modern patients.

Coley tried at least 13 different vaccine formulations over time, making it difficult to compare results.  “Although Coley, in his numerous publications, seldom gave full details of site, dosage, frequency, or duration of vaccine application, the optimal therapy regimen, with hindsight, seemed to be intratumoral, intramuscular, or intraperitoneal injections over long periods of time.”[10]

Coley selected his patients deliberately to maximize the chance of recovery; he favored sarcoma patients because the bacterial vaccine seemed to work best on them. Cases of spontaneous remission following erysipelas infections were also predominantly soft-tissue sarcomas.[16]

Coley’s preparations, known as “Coley Toxins”, were in use until 1963, when the Estes-Kefauver Act ruled that drugs had to prove safety and efficacy to be FDA-approved.[15]

A retrospective review [17] published in in Alternative Therapies in Health and Medicine compared 128 Coley cases from 1890 to 1960 with 1675 controls from SEER who received a cancer diagnosis in 1983. Patients were matched by age, site, stage, and radiation treatment status.  10-year survival rate was not significantly different for Coley’s patients vs. modern controls, which suggests that Coley toxins were of comparable efficacy to chemotherapy.

A 1971 retrospective study[18] of 47 patients with reticulum sarcoma of the bone, treated with Coley toxins before 1956, found a five-year survival rate of 64%.  22 cases (48%) achieved permanent results.  With surgery or radiation therapy alone, five-year survival rates were 32-38%.  As of 2015, reticulosarcoma, also known as lymphoma of the bone, has 89% five-year survival in stage I if treated with chemo + radiotherapy. But bone lymphoma is also often a sign of metastatic disease, which would have lower survival rates. 16 of the 47 cases in the 1971 study were metastatic.  The failures of Coley toxins tended to be briefer courses rather than longer ones, and intramuscular rather than intratumoral or intravenous.

More recent attempts to replicate the effectiveness of Coley toxins (also known as mixed bacterial vaccine or MBV) have been less successful. A Chinese study[20] in 1991 of 86 patients with hepatocellular carcinoma were randomized to either MBV or control; there was a nonsignificant trend towards better survival in the MBV group. An uncontrolled study [21] of MBV in 12 patients with refractory malignancies found one partial response, and a “dramatic improvement in performance status and disease stabilization” in a patient with AIDS and Kaposi’s sarcoma.  An uncontrolled German study[22] of 12 patients with NY-ESO-1 expressing tumors (6 melanoma, 2 sarcoma, 2 prostate cancer, 1 with head and neck cancer, 1 with bladder cancer) found one partial response after treatment with MBV.

Coley toxins are popular in alt-med circles, and the effects haven’t been replicated in a modern experiment. However, the historical data does seem to show dramatic effects, and it is mechanistically plausible that bacterial vaccines stimulate the immune system.  A point in defense of Coley toxins is that the few existing modern trials don’t copy what Coley did (repeated, intratumoral injections, calibrated to produce fever, with patients selected for sarcoma).  A controlled trial of Coley toxins under those conditions could be extremely valuable.

Endotoxin and Tumor Necrosis Factor

Endotoxin, also known as lipopolysaccharide, is a molecule found on the membrane of Gram-negative bacteria, which elicits a strong immune response in the host.  Endotoxin causes the release of inflammatory cytokines, fever, and in extreme cases septic shock.  It also has antitumor effects, strengthening the case that bacterial infection can cause cancer regression.

A study [24] of intravenously administered endotoxin found that it caused partial responses in 2 out of 18 patients with colorectal cancer.  Intravenous endotoxin caused one complete remission out of 37 patients [25] with colorectal and non-small-cell lung cancer.

Parenteral injection of bacterial endotoxin in mice reliably [26] causes necrosis of experimental tumors.  Spindle cell sarcoma (SA-1) and fibrosarcoma (Meth A) regress completely, while CaD2 (breast carcinoma) and BP3 (another kind of fibrosarcoma) grow unchanged.  Necrosis occurred in all tumors. Endotoxin does not cause tumor regression in T-cell deficient mice.  In mice whose tumors regressed, subsequent injection with cells from the same tumor did not grow, suggesting that sensitized T-cells are the cause of the tumor resistance.

Environmental exposure to endotoxin in Chinese workers in the textile industry is inversely associated with lung cancer risk (HR = 0.60, p = 0.002)[27].

The anti-tumor activity of endotoxin appears to be associated with tumor necrosis factor, or TNF.  In 1975 [28] it was observed that Bacillus Calmette-Guerin-infected mice treated with endotoxin produced a substance, dubbed TNF, which was as effective as endotoxin itself in causing regression of transplanted sarcomas in mice.

TNF is too dangerous to give patients intravenously, but it is effective on sarcomas when administered locally when combined with cytotoxic chemotherapy.  High-dose TNF-alpha administered[29] in isolation perfusion of the limbs of 23 patients with metastatic melanoma or soft-tissue sarcoma found 21 complete responses and 2 partial responses.  In 186 patients [30]with locally advanced soft-tissue sarcomas, isolated limb perfusion with tumor necrosis factor caused complete response in 18%, partial response in 57%, and limb salvage in 82%.

There certainly appears to be a TNF-mediated anti-tumor response, and it is suggestive (and in line with the evidence about spontaneous remissions and Coley toxins) that this effect is associated with fever and especially strong against sarcomas.

Conclusions

I don’t believe there’s a single well-established bacterial cancer treatment right now, but it does seem clear that bacterial infections, particularly febrile infections, and derived substances like endotoxin and TNF, can often cause cancer remissions, especially in sarcomas and some advanced cancers.  Additional “protocol engineering” followed by randomized trials might yield a reliable bacterial therapy.  In the contexts where they are effective, bacterial and bacterial-derived treatments seem to cause meaningful increases in survival time, whereas most targeted chemotherapies do not.

References

[1]Mellman, Ira, George Coukos, and Glenn Dranoff. “Cancer immunotherapy comes of age.” Nature 480.7378 (2011): 480-489.

[2]http://www.cancer.gov/about-cancer/treatment/research/car-t-cells

[3]https://en.wikipedia.org/wiki/Peregrine_Laziosi

[4]Challis, G. B., and H. J. Stam. “The spontaneous regression of cancer: a review of cases from 1900 to 1987.” Acta Oncologica 29.5 (1990): 545-550.

[5]Papac, Rose J. “Spontaneous regression of cancer.” Cancer treatment reviews22.6 (1996): 395-423.

[6]Bodurtha, A. J., et al. “A clinical, histologic, and immunologic study of a case of metastatic malignant melanoma undergoing spontaneous remission.” Cancer37.2 (1976): 735-742.

[7]Ifrah, Norbert, et al. “Spontaneous remission in adult acute leukemia.” Cancer56.5 (1985): 1187-1190.

[8]Wiernik, Peter H. “Spontaneous regression of hematologic cancers.” National Cancer Institute Monograph 44 (1976): 35-38.

[9]Mitterbauer, M., et al. “Spontaneous remission of acute myeloid leukemia after infection and blood transfusion associated with hypergammaglobulinaemia.”Annals of hematology 73.4 (1996): 189-193.

[10]Hobohm, Uwe. “Fever and cancer in perspective.” Cancer Immunology, Immunotherapy 50.8 (2001): 391-396.

[11] Maywald, O., et al. “Spontaneous remission in adult acute myeloid leukemia in association with systemic bacterial infection—case report and review of the literature.” Annals of hematology 83.3 (2004): 189-194.

[12]Tocci, G., et al. “Spontaneous remission of hepatocellular carcinoma after massive gastrointestinal haemorrhage.” Bmj 300.6725 (1990): 641-642.

[13]Ruckdeschel, John C., et al. “Postoperative empyema improves survival in lung cancer: documentation and analysis of a natural experiment.” New England Journal of Medicine 287.20 (1972): 1013-1017.

[14] Kleef, Ralf, et al. “Fever, cancer incidence and spontaneous remissions.”Neuroimmunomodulation 9.2 (2001): 55-64.

[15]http://www.cancerresearch.org/news-publications/our-blog/april-2015/whatever-happened-to-coleys-toxins

[16]Wiemann, Bernadette, and Charlie O. Starnes. “Coley’s toxins, tumor necrosis factor and cancer research: a historical perspective.” Pharmacology & therapeutics 64.3 (1994): 529-564.

[17]Richardson, Mary Ann, et al. “Coley toxins immunotherapy: a retrospective review.” Alternative therapies in health and medicine 5.3 (1999): 42.

[18]Miller, Theodore R., and Jesse T. Nicholson. “End results in reticulum cell sarcoma of bone treated by bacterial toxin therapy alone or combined with surgery and/or radiotherapy (47 cases) or with concurrent infection (5 cases).”Cancer 27.3 (1971): 524-548.

[19]Jamshidi, Khodamorad, et al. “Stage IE Primary Bone Lymphoma: Limb Salvage for Local Recurrence.” Archives of bone and joint surgery 3.1 (2015): 39.

[20]Tang, Zhao You, et al. “Preliminary result of mixed bacterial vaccine as adjuvant treatment of hepatocellular carcinoma.” Medical oncology and tumor pharmacotherapy 8.1 (1991): 23-28.

[21]Vas, H. Francis Ha, et al. “Clinical results and immunologic effects of a mixed bacterial vaccine in cancer patients.” Medical oncology and tumor pharmacotherapy 10.4 (1993): 145-158.

[22]Karbach, Julia, et al. “Phase I clinical trial of mixed bacterial vaccine (Coley’s toxins) in patients with NY-ESO-1 expressing cancers: immunological effects and clinical activity.” Clinical Cancer Research 18.19 (2012): 5449-5459.

[23]http://www.cancer.org/cancer/sarcoma-adultsofttissuecancer/detailedguide/sarcoma-adult-soft-tissue-cancer-survival-rates

[24]Engelhardt, Rupert, Andreas Mackensen, and Chris Galanos. “Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients.” Cancer research 51.10 (1991): 2524-2530.

[25]Otto, F., et al. “Phase II trial of intravenous endotoxin in patients with colorectal and non-small cell lung cancer.” European Journal of Cancer 32.10 (1996): 1712-1718.

[26]Berendt, MICHAEL J., ROBERT J. North, and DAVID P. Kirstein. “The immunological basis of endotoxin-induced tumor regression. Requirement for T-cell-mediated immunity.” The Journal of experimental medicine 148.6 (1978): 1550-1559.

[27]Astrakianakis, George, et al. “Lung cancer risk among female textile workers exposed to endotoxin.” Journal of the National Cancer Institute 99.5 (2007): 357-364.

[28]Carswell, E. A., et al. “An endotoxin-induced serum factor that causes necrosis of tumors.” Proceedings of the National Academy of Sciences 72.9 (1975): 3666-3670.

[29]Liénard, Danielle, et al. “High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma.” Journal of clinical oncology 10.1 (1992): 52-60.

[30]Eggermont, A. M., et al. “Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience.” Annals of surgery 224.6 (1996): 756.

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3 thoughts on “Bacterial Infections and Cancer Remissions

  1. Why research this rather than targeted immunotherapies? If the bacterial infections work by activating the immune system, we can get that effect more easily with an immune checkpoint blockade.
    Research towards targeted immunotherapies may include tracing TNF far enough downstream to figure out how it activates the immune system, and then developing a drug that acts through the same mechanism. But compared to that, the expected gains from directly testing TNF or other bacterial parts seems small.

    • Simplicity, really. If we go farther downstream there are more moving parts and more opportunities for error. We *know* bacterial infections alone can kill tumors, because it’s happened spontaneously without medical intervention. So (heuristically), it seems you want to go as close to the source as possible.

      The way I’m thinking about this is, suppose it’s the 1700s and you’ve noticed that people tend to get less scurvy if they eat citrus fruits. You *could* try to figure out what the scurvy-curing ingredient in citrus was, and isolate Vitamin C. But that will take a long time and perhaps require scientific techniques you don’t yet have. So what you do *now*, is tell sailors to eat limes.

      • I like the scurvy example. Sailors eating Sicilian lemons had much less scurvy, but switching to West Indian limes reduced the effect. Using lime juice rather than fresh fruit reduced the effect, especially if it touched copper. Limes is too upstream; it’s not reliable. I suspect many of the treatments discussed in this post to be similar. But if I had any real evidence I’d have included it in the first post.
        Here’s the way I’m imagining it:
        Infection –> Immune activation –> immune system kills cancer cells
        But we already know how to achieve that central causal node; administer ipilimumab. And we’re already doing that clinically, with dramatic improvements in melanoma survival, and I think much less good news in other cancers. If that’s what activating the immune system gets us, what more could we expect to gain from activating it less directly?
        But, as I write this out, I realize I’m thinking of this very naively. Because of course infection, mixed bacterial vaccine, endotoxin, and ipilimumab all activate that central causal node very reliably, right? But I do not expect that they are doing quite the same thing as each other (otherwise how could I favor ipilimumab over other means of immune activation?). But I don’t really know what the differences are. Hmm.
        Some of that stuff is way cheaper than ipilimumab too. I wonder if we’d be using it if it was patentable.
        Source for the scurvy stuff: http://www.thenakedscientists.com/HTML/articles/article/forgotten-knowledge/
        Same link as before for ipilimumab efficacy in melanoma: http://jco.ascopubs.org/content/early/2015/02/18/JCO.2014.56.6018.short

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