Tag Archives: immunotherapy

T-Cells and cancer Everyone has heard about the miraculous stories of recovery from cancer using immunotherapy. Immunotherapy involves giving the sick person substances which stimulate the person's own immune system to battle the cancer. And when it works, it's wonderful. But...there's another side - a dark side of the harms from these treatments - that is rarely discussed, and why we should be very careful going forward.

Here are two articles that do point out the problems - such as in some people the immunotherapy actually accelerates the cancer being treated (called "hyperprogression of tumors"). Studies suggest that these people share certain genetic characteristics or they are over the age of 65. In general, many patients undergoing immunotherapy have side-effects, some even developing life-threatening ones, from the treatments. Also, most patients do not respond to the immunotherapy treatments, for reasons that remain largely unknown. Obviously more studies are needed. Remember, this field is in its infancy.

Excerpts from Bob Tedeschi's article, from STAT: Cancer researchers worry immunotherapy may hasten growth of tumors in some patients

For doctors at the University of California, San Diego, it was seemingly a no-lose proposition: A 73-year-old patient’s bladder cancer was slowly progressing but he was generally stable and strong. He seemed like the ideal candidate for an immunotherapy drug, atezolizumab, or Tecentriq, that had just been approved to treat bladder cancer patients. Doctors started the patient on the drug in June. It was a spectacular failure: Within six weeks, he was removed from the drug, and he died two months later.

In a troubling phenomenon that researchers have observed in a number of cases recently, thetreatment appeared not only to fail to thwart the man’s cancer, but to unleash its full fury. It seemed to make the tumor grow faster. The patient’s case was one of a handful described last week in the journal Clinical Cancer Research. Of the 155 cases studied, eight patients who had been fairly stable before immunotherapy treatment declined rapidly, failing the therapy within two months. Six saw their tumors enter a hyperactive phase, where the tumors grew by between 53 percent and 258 percent.

“There’s some phenomenon here that seems to be true, and I think we cannot just give this therapy randomly to the patient,” the author of the study, Dr. Shumei Kato, an oncologist at UC San Diego, said in an interview with STAT. “We need to select who’s going to be on it.” .... But similar findings were published last year by cancer researchers at the Gustave Roussy Institute in France. These results were considered controversial by some, since they hadn’t been widely confirmed by other oncologists.

In the latest Clinical Cancer Research findings, those who experienced the hyperprogression of tumors, as the phenomenon is known, shared specific genetic characteristics. In all six patients with so-called amplifications in the MDM2 gene family, and two of 10 patients with alterations in the EGFR gene, the anti-PD-1 or anti-PD-L1 immunotherapies quickly failed, and the patients’ cancers progressed rapidly. ....Doctors who prescribe immunotherapies may be able to identify at-risk patients by submitting tumors for genetic testing, Kato and his coauthors suggested.

The findings published last year by the Gustave Roussy team also appeared in Clinical Cancer Research. In that study, of 131 patients, 12 patients, or 9 percent, showed hyperprogressive growth after taking anti-PD-1 or anti-PD-L1 immunotherapies. The lead author of that study, Stephane Champiat, acknowledged that the research so far raises more questions than it answers. ... Champiat suggested factors that could be associated with the effect. In his study’s patients, for instance, those who were older than 65 showed hyperprogressive growth at twice the rate of younger patients.

Oncologists studying this phenomenon said it could complicate treatment strategies, becausesome patients who receive immunotherapies can exhibit what’s known as “pseudo-progression,” in which tumor scans reveal apparent growth. In reality, however, the scans are instead showing areas where the cancer is being attacked by armies of immune cells. Roughly 10 percent of melanoma patients on immunotherapies, for instance, experience this phenomenon.

Jimmy Carter is perhaps the best-known immunotherapy success story. But most patients do not respond to the immunotherapy treatments, for reasons that remain largely unknown. In a study by Prasad and Dr. Nathan Gay, also of Oregon Health and Science University, nearly 70 percent of Americans die from forms of cancer for which there is no immunotherapy option, and for the rest who do qualify forimmunotherapy, only 26 percent actually see their tumors shrink.

And while immunotherapies typically include less intrusive side effects than chemotherapy, those side effects, when they happen, can be life-threatening. Researchers have reported cases in which immunotherapies attacked vital organs, including the colon, liver, lungs, kidney, and pancreas, with some patients experiencing acute, rapid-onset diabetes after receiving the treatments. But in those cases, the treatments were at least attacking the cancer. Such reports didn’t raise the specter of these treatments possibly working on the cancer’s behalf to shift it into overdrive.

 T-Cells and cancer A group of killer T cells (green and red) surrounds a cancer cell (blue, center). Credit: NIH.

From Health News Review: Cancer immunotherapy: more reason for concern?

Immunotherapy for cancer — which basically involves manipulating our immune system to attack cancer cells — is ever so slowly creeping toward the scrutiny phase. This slow crawl is something we reported on four months ago. With few exceptions, like this deep dive by the New York Times (the Cell Wars series ), we found many journalists completely overlooked the harms (some life-threatening) of this oft-vaunted treatment.

 The possibility of giving microbes in the future (whether bacteria, viruses, or fungi) to treat cancer is amazing. Of course big pharma is pursuing this line of research, which is called immunotherapy (stimulating the body's ability to fight tumors). The Bloomberg Business article discusses a number of big pharma companies entering the field and their main focus. The study in the journal Science finding that giving common beneficial bacteria (Bifidobacterium breve and Bifidobacterium longum) to mice to slow down melanoma tumor growth is a first step. The researchers themselves said that the 2 common beneficial bacteria species exhibited anti-tumor activity in the mice and was as effective as an immunotherapy in controlling the growth of skin cancer. But note that the bacteria needed to be live. Stay tuned....

From Bloomberg News: How Gut Bacteria Are Shaking Up Cancer Research

Top scientists at Roche Holding AG and AstraZeneca Plc are sizing up potential allies in the fight against cancer: the trillions of bacteria that live in the human body. "Five years ago, if you had asked me about bacteria in your gut playing an important role in your systemic immune response, I probably would have laughed it off," Daniel Chen, head of cancer immunotherapy research at Roche’s Genentech division, said in a phone interview. "Most of us immunologists now believe that there really is an important interaction there."

Two recent studies published in the journal Science have intrigued Chen and others who are developing medicines called immunotherapies that stimulate the body’s ability to fight tumors.In November, University of Chicago researchers wrote that giving mice Bifidobacterium, which normally resides in the gastrointestinal tract, was as effective as an immunotherapy in controlling the growth of skin cancer. Combining the two practically eliminated tumor growth. In the second study, scientists in France found that some bacterial species activated a response to immunotherapy, which didn’t occur without the microbes.

That’s increased drugmakers’ interest in the human microbiome -- the universe of roughly 100 trillion good and bad bacteria, fungi and viruses that live on and inside the body. Roche is already undertaking basic research in the field and plans to investigate the microbiome’s potential for cancer treatment, Chen said."Certainly, we are already scanning the space for interesting opportunities as the science continues to emerge," he said. "We are very interested in testing these in a controlled setting."

Another startup, 4D Pharma Plc, in November said it had discovered a bacterium that produces a response comparable to that of an immunotherapy in animal tests for breast and lung cancers. The London-listed company plans to start trials in patients by the end of this year. To support research in autoimmune and neurological diseases, in addition to cancer, the company has raised over 100 million pounds ($140 million) from investors over the last two years, CEO Duncan Peyton said in a phone interview.

"We are in active discussions with the usual suspects in the immunotherapy space," Belichard said in an interview in London. Those active in the field include a wide range of pharma companies including AstraZeneca, Roche, Bristol-Myers Squibb Co., and Merck & Co....The sheer number of bacteria, some of which could actually switch off an immune response, and the question of how much bacteria is needed, make it a complex area of research, Roche’s Chen said. It’s possible that the same bacteria could induce both harmful and helpful responses, depending on the patient, he said. Still, "it’s one of the most interesting developments we’ve seen in science over the last several years," he said.

The Abstract and excerpts of the article in the journal Science: Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.

T cell infiltration of solid tumors is associated with favorable patient outcomes, yet the mechanisms underlying variable immune responses between individuals are not well understood. One possible modulator could be the intestinal microbiota. We compared melanoma growth in mice harboring distinct commensal microbiota and observed differences in spontaneous antitumor immunity, which were eliminated upon cohousing or after fecal transfer. Sequencing of the 16S ribosomal RNA identified Bifidobacterium as associated with the antitumor effects. Oral administration of Bifidobacterium alone improved tumor control to the same degree as programmed cell death protein 1 ligand 1 (PD-L1)-specific antibody therapy (checkpoint blockade), and combination treatment nearly abolished tumor outgrowth. Augmented dendritic cell function leading to enhanced CD8(+) T cell priming and accumulation in the tumor microenvironment mediated the effect. Our data suggest that manipulating the microbiota may modulate cancer immunotherapy.

Bifidobacterium-treated mice displayed significantly improved tumor control in comparison to non-Bifidobacterium treated counterparts which was accompanied by robust induction of tumor specific T cells in the periphery and increased accumulation of antigen -specific CD8+T cells within the tumor. These effects were durable for several weeks....Heat inactivation of the bacteria prior to oral administration also abrogated the therapeutic effect on tumor growth and reduced tumor-specific T cell responses to baseline, suggesting that the antitumor effect requires live bacteria. As an alternative strategy, we tested the therapeutic effect of B. breve and B. longum strains obtained from the ATCC, which also showed significantly improved tumor control.... Oral administration of Lactobacillus murinus to TAC mice, which was not among the overrepresented taxa in JAX (Jackson Laboratory)-fed mice, had no effect on tumor growth or on tumor-specific T cell responses, suggesting that modulation of antitumor immunity depends on the specific bacteria administered. Collectively, these data point to Bifidobacterium as a positive regulator of antitumor immunity in vivo.

Our studies demonstrate an unexpected role for commensal Bifidobacterium in enhancing antitumor immunity in vivo. Given that beneficial effects are observed in multiple tumor settings, and that alteration of innate immune function is observed, this improved antitumor immunity could be occurring in an antigen-independent fashion. The necessity for live bacteria may imply that Bifidobacterium colonizes a specific compartment within the gut that enables it to interact with host cells that are critical for modulating DC function, or to release soluble factors that disseminate systemically leading to improved DC function.

(thumbnail) Bifidobacterium longum. Courtesy of Mark Schell, Univ.of Georgia

 Bifidobacterium breve Courtesy of Dr. Wayne Modler