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Cat Lady Not So Crazy After All: Cancer Breakthrough…in the Litter Box?!

By Alison Wagner, PhD, Medical Writer

kitten in litter box

To be clear, it is not the actual waste of the cat that is so intriguing (although my dog would beg to differ). It is Toxoplasma gondii (T. gondii), a parasite that requires a cat host during its lifecycle and is expelled in the feces, that has scientists from different fields, including behavioral neuroscience, immunology, and oncology, interested.

T. gondii must begin and complete its lifecycle in cats, but any warm-blooded animal can serve as an intermediate host. In these instances, the animal typically consumes the oocyst form of T. gondii. Once consumed, the oocyst ruptures and there is a brief period of fast replication and invasion of tissues (tachyzoite stage). The host’s immune response then triggers T. gondii to transform into the less active bradyzoite or chronic infection stage.
life cycle

Lifecycle of Toxoplasma gondii. (LadyofHats, Wikimedia Commons)

T. gondii is best known for giving pregnant women a great excuse to hand over litter box duties to someone else, and for good reason: first-time maternal infection with T. gondii during pregnancy can have significant effects on the developing fetus or even cause miscarriage. These effects are at least partially due to an inflammatory reaction of the maternal immune system to the parasite. People with immune deficiencies, such as HIV patients, are also at risk for complications associated with T. gondii infection, but the widespread belief until recently was that infection with T. gondii in healthy adults, though common (currently up to a third of the global population), was generally asymptomatic.

However, researchers noted that mice infected with T. gondii showed a peculiar behavior – they lost their fear response to cats (specifically, to cat odors). Causing that change in behavior is advantageous to T. gondii because the lack of fear would improve the odds that a cat could kill and eat the mouse, which in turn would perpetuate the parasite’s lifecycle. Interestingly, this effect lasted long after T. gondii had been cleared from the body, indicating that it is not a direct effect of the parasite itself. The authors of the study suggest that the immune system response that continues after the parasite is eliminated might be the culprit, rather than the actual parasite, which would explain why the behavior persists.

If T. gondii can make mice behave contrary to their natural instincts, what about humans? As it turns out, infection with T. gondii does appear to alter human behavior. For instance, infected men are said to be on average more jealous and more likely to disregard rules, while infected women are typically more warm and outgoing. T. gondii infection is also linked to an increased risk of schizophrenia, possibly due to an inflammatory response that increases release of dopamine, the key neurotransmitter known to be involved in schizophrenia.

Many media outlets immediately linked these changes to “crazy cat lady syndrome” (see here, here, here, and here). However, in my humble opinion, the behavioral changes don’t fit the stereotypical crazy cat lady. The characteristics I associate with CCLs include “introverted,” “unsocial,” and “misanthropic,” not “warm and outgoing.”

As fascinating as the effects of T. gondii on behavior are, what does that have to do with cancer and a potential new therapy? As Heather Lasseter discussed in her cancer immunotherapy post, many of the most promising cancer vaccines in development now address the problem of inhibition of normal T-cell response by molecules like CTLA-4 and PD-1 that are released by the cancer cells. And as I discussed in my last post (“Why Wolverine Will Never Get Cancer”), the immune system is intimately involved in whether cancer cells survive and thrive or not. Figuring out how to manipulate the immune system accordingly would be an enormous breakthrough in cancer therapy.

It turns out that T. gondii elicits a very specific reaction from the immune system. Rather than trying to “hide,”  T. gondii activates T cells and other inflammatory responders such as natural killer (NK) cells. This provokes the immune system to do exactly what it is supposed to do – attack invaders – and  limits the growth of T. gondii into surrounding tissue. It may seem like the worst war strategy ever for T. gondii to basically wave a flag at the enemy while shouting taunts. However, this strategy works because of the parasite’s specific lifecycle (see above) – the immune response to the invader actually aids in its transformation into bradyzoites, an essential part of that lifecycle.

Because T. gondii is so excellent at producing T-cell and NK-cell response, it can induce the exact conditions needed to stimulate the immune system and overcome the inhibitory signals from cancer cells. Indeed, researchers using a non-replicating* form of T. gondii as a basis for a cancer vaccine found that mice given this vaccine were able to achieve extraordinarily high levels of survival against extremely aggressive cancers. Immune cells in the tumor microenvironment showed higher levels of activation, indicating that the T. gondii–based vaccine had jump-started the immune system into attacking the tumor cells more aggressively and causing tumor regression. These kinds of studies have not yet been conducted in human patients – the science is still very much in the preclinical phase – but given that mice and humans are both intermediate hosts to T. gondii and show similar immune responses to the parasite, it is reasonable to anticipate positive results as this potential vaccine is tried in humans.

*The non-replicating part is key here – giving people a systemic parasitic infection is generally not considered good practice, especially when those patients are potentially immunocompromised. The vaccine that is in preclinical development is based on T. gondii, but does not produce a live infection, because a key gene for replication of T. gondii is removed.

So what does this all mean? Some might say: eat cat poop to prevent cancer. I would suggest holding off on that. It’s likely that the T. gondii (or T. gondii–like vaccine) would need to be present directly at the tumor site rather than distributed systemically; also, most indoor house cats don’t actually have T. gondii (sorry, pregnant ladies hoping to get out of litter box duty). You would then have eaten cat poop for no good reason, and that’s just disgusting. However, we can conclude that while we are making progress on understanding the immune system and how it can be a major player in cancer therapeutics, there may just be a few shortcuts we can take, provided by nature (and cat poop).

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Breakthrough of the Year – Cancer Immunotherapy?

By Heather Lasseter, PhD, Medical Writer

Are advances in cancer immunotherapy a top scientific achievement of the year? 

Editors of Science certainly think so, heralding “cancer immunotherapy” as 2013’s Breakthrough of the Year: “This year marks a turning point in cancer, as long-sought efforts to unleash the immune system against tumors are paying off – even if the future remains a question mark.”

Picture4

Awareness ribbons representing lung, breast, cervical, brain, kidney, prostate, and colon cancer, and melanoma (adapted from MesserWoland, wikimediacommons.org).

With June as Cancer Immunotherapy Month (designated by the Cancer Research Institute), cancer immunotherapy is a hot topic in oncology – especially as research here may lead to major treatment breakthroughs for many cancers. But currently approved treatment comes with a hefty price tag: approximately $120,000 for a round of therapy. Given the potentially modest impact on survival (for instance, on the order of several months), does cancer immunotherapy truly represent a key breakthrough of 2013?

 

Immune destruction – a hallmark of cancer

Hallmarks

Hanahan and Weinberg’s hallmarks of cancer (Cell. 2011;144:646-674).

Avoiding immune destruction was recognized as one of the emerging hallmarks of cancer by Hanahan and Weinberg in 2011. Cancer cells survive and thrive through their well-known characteristics of ceaseless proliferation and invasion, as well as their ability to  evade the body’s natural defenses. While the immune system is tasked with cleaning up cells gone rogue, cancer cells not only escape these defense mechanisms, but hijack the immune system for their own advantage (i.e., tumor angiogenesis).

Cancer immunotherapy – the idea of targeting the body’s own immune system to attack cancerous cells – has been around for about 20 years. But with poor understanding of mechanisms for immune activation and hesitancy from pharmaceutical companies, cancer immunotherapy has only recently gained traction.

Early work by cancer immunologist James Allison (published in Science in 1996) sparked the renaissance in cancer immunotherapy. He demonstrated that administering antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4) in vivo caused the rejection of tumor cells. However, it was not until 15 years later that ipilimumab – a monoclonal antibody that targets CTLA-4 on T cells – became the first immunotherapy approved for treating metastatic melanoma. While cancer cells release antigens that activate the immune system, they also produce proteins that bind to CTLA-4, thereby preventing a full-out immune attack. Ipilimumab blocks this inhibitory signal, letting the immune system do its job. The result: cancer cell death.

Clinical trials are currently underway to assess efficacy of ipilimumab and other agents targeted to  reverse immune checkpoint pathways, which cancer cells exploit to inhibit the immune system. These are being assessed in the treatment of melanoma, lymphoma, lung, breast, gastric, and prostate cancers. Such agents include antibodies against programmed death-1 (PD-1), a molecule on T cells that puts the brakes on T-cell activation. Moreover, combination therapy of an anti-CTLA-4 plus anti-PD-1 has produced a “rapid and deep tumor regression” in patients with advanced melanoma, according to a study published in the New England Journal of Medicine. In addition, more recent advances involve genetically engineering T cells to express chimeric antigen receptors (CARs). CARs permit T cells to specifically target antigens on tumor cells.

One exciting possibility may be personalized immunotherapy

In a recent study in Science, CD4+ T helper cells were identified that responded to a mutated antigen found in the cancer cells of a patient with metastatic epithelial cancer. These mutation-reactive immune cells were extracted, amplified in cell cultures, and transfused back to the patient using a technique called adoptive cell transfer. The results were remarkable: the tumor regressed and then stabilized until 13 months post-transfusion. Following disease progression and a second round of immunotherapy, the tumor again regressed (last follow-up of 6 months).

Adoptive T-cell therapy (Simoncaulton, wikimediacommons.org).

Broadening the cancer immunotherapy pool

In the last several years, many groups have launched themselves into this line of research. As part of its Moon Shots Program, the University of Texas MD Anderson Cancer Center has collaborated in 2014 with four large companies – Johnson & Johnson, Pfizer, GlaxoSmithKline, and AstraZeneca’s MedImmune – to accelerate the development of immunotherapies and reduce cancer deaths. And cancer immunotherapy was a hot topic at the ASCO Annual Meeting, with large pharmaceutical companies sharing promising clinical data:

  • Bristol-Myers Squibb: Combination of the PD-1 immune checkpoint inhibitor nivolumab plus ipilimumab in a phase 1b trial shrank tumors in 42% of patients with advanced melanoma and produced 1- and 2-year overall survival of 85% and 79%, respectively.
  • Merck: In a phase 1b trial, the anti-PD-1 antibody pembrolizumab (MK-3475) reduced tumors in 51% of patients with PD-ligand 1 (PD-L1)-positive advanced head and neck cancer and produced a best overall response rate (ORR) of 20%.
  • RocheIn a phase 1 trial, the anti-PD-L1 therapy MPDL3280A shrank tumors in 43% of patients with PD-L1-positive metastatic bladder cancer and produced an ORR of 52%.
  • AstraZeneca: Although the clinical data were limited, AstraZeneca described the phase 1 dose-escalation trial assessing the PD-L1 inhibitor MEDI-4736 plus CTLA-4 inhibitor tremelimumab in patients with advanced solid tumors.

Moving cancer immunotherapy forward

While these results are promising, cancer immunotherapy only benefits a certain population of patients – and the reasons why are poorly understood. For instance, treatment efficacy may be impaired by the presence of mutations in a patient’s tumor that confer protection against antitumor immunity. As stated by Tjin et al in Cancer Immunology Research, “Immunotherapy is a promising strategy… but the modest clinical responses so far call for improvement of therapeutic efficacy.”

So what’s next for cancer immunotherapy?

It will be necessary to develop biomarkers for patients who will show a clinical benefit, increase the proportion who respond to treatment, and develop more potent treatment strategies. Treatment strategies will likely involve combination therapies, adding an immune system booster, and streamlining the development of targeted treatments. Progress to broaden and optimize the benefits of cancer immunotherapy is needed to make it worthy of being called the “Breakthrough of the Year.”