Mapping the cancer genome wilderness

A huge cancer genome project has highlighted how DNA that doesn’t code for proteins is still important for keeping our cells on Read more

Stem-like CD8 T cells stay in lymph nodes/spleen

Virus-specific CD8 T cells accumulate in lymph nodes and in other organs, without circulating in abundance in the Read more

To fight cancer, mix harmless reovirus with 'red devil'

The GDBBS symposium included a talk about the next step: attaching the souped-up reovirus to Read more

cancer immunotherapy

Stem-like CD8 T cells stay in lymph nodes/spleen

In a mouse model of chronic viral infection, there are very few virus-specific killer T cells in the blood, Emory Vaccine Center scientists report in a new paper in PNAS. This has implications for efforts to enhance cancer immunotherapy, because in both chronic viral infection and cancer, the same types of exhausted T cells accumulate.

CD8 T cells in lymphoid tissue (spleen) – from Im et al Nature (2016)

Vaccine Center director Rafi Ahmed’s lab has learned a great deal about exhausted T cells by studying the LCMV (lymphocytic choriomeningitis virus) model. In this situation, virus-specific CD8 T cells accumulate in lymph nodes and in other organs, without circulating in the blood, because they acquire a residency program, the PNAS authors write. Postdoc Sejin Im’s 2016 paper defined these “stem-like” cells – he is the first author of the new one as well.

A related phenomenon can be seen in the Kissick lab’s recent paper on immune “outposts” in kidney and other urologic tumors. The stem-like cells stay within the tumor and give rise to similar progeny. One consequence may be that treatments aimed at reactivating those cells need to get inside the tumor.

Posted on by Quinn Eastman in Immunology Leave a comment

Immune outposts inside tumors predict post-surgery outcomes

The immune system establishes “forward operating bases”, or lymph node-like structures, inside the tumors of some patients with kidney and other urologic cancers, researchers at Winship Cancer Institute of Emory University have discovered.

From left to right: Carey Jansen, Nataliya Prokhnevska, Hadyn Kissick and Viraj Master

Patients with well-supported immune cells in their tumors are more likely to control their cancers’ growth for a longer time — findings that could guide treatment decisions after surgery for kidney cancer. In addition, ongoing work has found the observation is broadly applicable to many cancer types, and it could help researchers expand the dramatic but sparse benefits of cancer immunotherapy to more people.

The results were published Wednesday, Dec. 11 in Nature.

“We knew that if there are more T cells in a tumor, the patient is likely to respond better to cancer immunotherapy,” says lead author Haydn Kissick, PhD. “But we were looking at a more basic question: why do some tumors have lots of T cells in them, and others don’t?”

Kissick is assistant professor of urology and microbiology and immunology at Emory University School of Medicine, Emory Vaccine Center and Winship Cancer Institute. His lab collaborated with surgeons and oncologists at Winship to examine tumor samples removed from patients with kidney, prostate and bladder cancer.

CD8 T cells hunt down and eliminate intruders – in this case, cancer cells. In patients with high levels of CD8 T cells residing in their tumors, their immune systems appeared to be better trained to suppress cancer growth after surgery, when small numbers of cancer cells (micrometastases) may be lurking elsewhere in the body. The cancers of those who had lower levels of CD8 T cells tended to progress four times more quickly after surgery than those with higher levels.

The finding has important implications, says Viraj Master, MD, who performed most of the kidney cancer surgeries. In this situation, additional treatments are not performed unless or until kidney cancer reappears, says Master, who is Fray F. Marshall Chair and professor of urology at Emory University School of Medicine and Winship’s Director of Integrative Oncology and Survivorship.

“Even after potentially curative surgery for aggressive kidney cancers, a significant fraction of patients will experience cancer recurrence,” he says. “But with this information, we could predict more confidently that some people won’t need anything else, thus avoiding overtreatment. However, on the basis of these findings, for others who are at higher risk of recurrence, we could potentially scan at more regular intervals, and ideally, design adjuvant therapy trials.”

The findings also provide insights for scientists interested in how the immune system successfully controls some cancers, but with others, the T cells become increasingly exhausted and ineffective.

“This study may lead to new insights into why immunotherapy can be so effective in some cancer types, but rarely works in others such as prostate cancer, and may highlight a path forward for developing more effective immunotherapy treatments,” says Howard Soule, PhD, executive vice president and chief science officer for the Prostate Cancer Foundation, which supported the Winship team’s work.

Kissick and his colleagues were surprised to find “stem-like” T cells, or precursors of exhausted cells, inside tumor samples. Stem-like T cells are the ones that proliferate in response to cancer immunotherapy drugs, which can revive the immune system’s ability to fight the cancer.

Tumor sample with high level of T cell infiltration. Red = CD8, yellow = MHC class II, a sign of APCs

“Lymph nodes are like ‘home base’ for the stem-like T cells,” says Carey Jansen, an MD/PhD student who is the first author of the Nature paper. “We had expected that the stem-like cells would stay in lymphoid tissue and deploy other T cells to infiltrate and fight the cancer. But instead, the immune system seems to set up an outpost, or a forward base, inside the tumor itself.”

The researchers found that other immune cells called “antigen-presenting cells” or APCs, which are usually found within lymph nodes, can also be seen within tumors. APCs help the T cells figure out when and what to attack. Like high numbers of CD8 T cells, high numbers of APCs in tumors were also a predictor of longer progression-free survival in kidney cancer patients.

The APCs and the stem-like cells were usually together within the same “nests,” in a way that resemble how the two types of cells interact in lymph nodes. This relationship was apparent in kidney cancers and also in samples from prostate and bladder cancers.

“The question of how the stem-like cells get into a tumor was not answered, but we do think that the APCs support the stem-like cells and are necessary for their maintenance,” Kissick says. “Given that these are the cells responsive to cancer immunotherapy agents, focusing on the relationship between the APCs and the T cells within the tumors could be valuable.”

Additional co-authors include: graduate student Nataliya Prokhnevska, urology chair Martin Sanda, MD and biostatistician Yuan Liu, PhD.

The research was supported by the National Cancer Institute (R00CA197891, U01CA113913), the Prostate Cancer Foundation, Swim Across America, the James M. Cox Foundation, James C. Kennedy, the Dunwoody Country Club Senior Men’s Association and an educational grant from Adaptive Technologies.

 

 

Posted on by Quinn Eastman in Cancer, Immunology Leave a comment

Transition to exhaustion: clues for cancer immunotherapy

Research on immune cells “exhausted” by chronic viral infection provides clues on how to refine cancer immunotherapy. The results were published Tuesday, Dec. 3 in Immunity.

Scientists at Emory Vaccine Center, led by Rafi Ahmed, PhD, have learned about exhausted CD8 T cells, based on studying mice with chronic viral infections. In the presence of persistent virus or cancer, CD8 T cells lose much of their ability to fight disease, and display inhibitory checkpoint proteins such as PD-1 on their surfaces. PD-1 is targeted by cancer immunotherapy drugs, such as pembrolizumab and nivolumab, which allow CD8 T cells to regain their ability to attack and kill infected cells and cancers.

Those drugs are now FDA-approved for several types of cancer, yet some types of tumors do not respond to them. Studying exhausted CD8 T cells can help us understand how to better draw the immune system into action against cancer or chronic infections.

In previous research, Ahmed’s lab found that exhausted cells are not all alike, and the diversity within the exhausted T cell pool could explain variability in responses to cancer immunotherapy drugs. Specifically, they observed that a population of “stem-like” cells proliferated in response to PD-1-blocking drugs, while a more differentiated population of exhausted cells stayed inactive. The stem-like cells are responsible for maintaining the exhausted T cell population, but cannot kill virus-infected or tumor cells on their own.

The current paper defines a transitional stage in between the stem-like and truly exhausted cells. The truly exhausted cells are marked by a molecule called CD101, and are unable to migrate to sites of infection and contain lower amounts of proteins needed to kill infected or tumor cells.

“The transitional cells are not completely exhausted,” says postdoctoral fellow Will Hudson, PhD, first author of the Immunity paper. “They are still capable of proliferating and performing their ‘killer cell’ functions. In our experiments, they contribute to viral control.”

The transitional cells, lacking CD101, could be a good marker for response to PD-1 blocking drugs, Hudson says. Enhancing the proliferation or survival of these cells, or preventing their transition to lasting exhaustion, may be a novel therapeutic strategy for cancer. Read more

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Exotic immune systems are big business

What timing! Just when our feature on Max Cooper and lamprey immunology was scheduled for publication, the Japan Prize Foundation announced it would honor Cooper and his achievements.

Cooper was one of the founders of modern immunology. We connect his early work with his lab’s more recent focus on lampreys, primitive parasites with surprisingly sophisticated immune systems.

Molecules from animals with exotic immune systems can be big business, as Andrew Joseph from STAT News points out. Pharmaceutical giant Sanofi recently bought a company focused on nanobodies, originally derived from camels, llamas and alpacas, for $4.8 billion.

Lampreys’ variable lymphocyte receptors (VLRs) are their version of antibodies, even though they look quite different in molecular terms. Research on VLRs and their origins may seem impractical. However, Cooper’s team has shown their utility as diagnostic tools, and his colleagues have been weaponizing them, possibly for use in cancer immunotherapy.

CAR-T cells have attracted attention for dramatic elimination of certain types of leukemias from the body and also for harsh side effects and staggering costs; see this opinion piece by Georgia Tech’s Aaron Levine. Now many research teams are scheming about how to apply the approach to other types of cancers. The provocative idea is: replace the standard CAR (chimeric antigen receptor) warhead with a lamprey VLR.

Read more

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Four hot projects at Emory in 2017

Once activated by cancer immunotherapy drugs, T cells still need fuel (CD28)

— Rafi Ahmed’s lab at Emory Vaccine Center. Also see T cell revival predicts lung cancer outcomes. At Thursday’s Winship symposium on cancer immunotherapy, Rafi said the name of the game is now combinations, with an especially good one being PD-1 inhibitors plus IL2.

Pilot study shows direct amygdala stimulation can enhance human memory

— Cory Inman, Joe Manns, Jon Willie. Effects being optimized, see SFN abstract.

Immune responses of five returning travelers infected by Zika virus

— Lilin Lai, Mark Mulligan. Covered here, Emory Hope Clinic and Baylor have data from more patients.

Frog slime kills flu virus

— Joshy Jacob’s lab at Emory Vaccine Center. A follow-up peptide with a name referencing Star Wars is coming.

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Cancer immunotherapy responses in the clinic: T cell revival as predictor

In lung cancer patients who were taking immunotherapy drugs, testing for revived immune cells in their blood partially predicted whether their tumors would shrink. The results were published online by PNAS on April 26.

This finding comes from a small study of 29 patients, who were being treated at Winship Cancer Institute of Emory University with drugs blocking the PD-1 pathway, also known as checkpoint inhibitors.

The study supports a straightforward idea: if tumor-specific CD8 T cells appear to respond to the drug (nivolumab, pembrolizumab or atezolizumab), that’s a good sign. This avenue of investigation may also help researchers figure out why some patients do not benefit from checkpoint inhibitor drugs, and how to combine those drugs with other treatments to increase response rates.

While looking for activated immune cells in the blood is not yet predictive enough for routine clinical use, such tests could provide timely information. Monitoring the immune response could potentially help oncologists and patients decide, within just a few weeks of starting immunotherapy drugs, whether to continue with the treatment or combine it with something else, says co-senior author Suresh Ramalingam, MD, Winship’s deputy director.

“We hypothesize that re-activated CD8 T cells first proliferate in the lymph nodes, then transition through the blood and migrate to the inflamed tissue,” says Rafi Ahmed, PhD, director of the Vaccine Center and a Georgia Research Alliance Eminent Scholar. “We believe some of the activated T cells in patients’ blood may be on their way to the tumor.”

The rest of the Emory Vaccine Center/Winship Cancer Institute press release is here. A few additional points: Read more

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Revived T cells still need fuel

Cancer immunotherapy drugs blocking the PD-1 pathway – known as checkpoint inhibitors – are now FDA-approved for melanoma, lung cancer and several other types of cancer. These drugs are often described as “releasing the brakes” on dysfunctional T cells.

A new study from Emory Vaccine Center and Winship Cancer Institute researchers shows that even if the PD-1-imposed brakes are released, the tumor-specific T cells still need “fuel” to expand in numbers and restore effective immune responses. That fuel comes from co-stimulation through a molecule called CD28.

The results were published Thursday by the journal Science.

Despite the success of PD-1-targeting drugs, many patients’ tumors do not respond to them. The study’s findings indicate that CD28’s presence on T cells could be a clinical biomarker capable of predicting whether drugs targeting PD-1 will be effective. In addition, the requirement for CD28 suggests that co-stimulation may be missing for some patients, which could guide the design of combination therapies.

For the rest of our press release and quotes from authors Rafi Ahmed, Alice Kamphorst and Suresh Ramalingam, please go here. For some additional links and thoughts on PD-1 and CD28, read on:

Read more

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Lab Land looking back: Top ten themes for 2014

It is a privilege to work at Emory and learn about and report on so much quality biomedical research. I started to make a top 10 for 2014 and had too many favorites. After diverting some of these topics into the 2015 crystal ball, I corralled them into themes.
1. Cardiac cell therapy
PreSERVE AMI clinical trial led by cardiologist Arshed Quyyumi. Emory investigators developing a variety of approaches to cardiac cell therapy.
2. Mobilizing the body’s own regenerative potential
Ahsan Husain’s work on how young hearts grow. Shan Ping Yu’s lab using parathyroid hormone bone drug to mobilize cells for stroke treatment.
3. Epigenetics
Many colors in the epigenetic palette (hydroxymethylation). Valproate – epigenetic solvent (anti-seizure –> anti-cancer). Methylation in atherosclerosis model (Hanjoong Jo). How to write conservatively about epigenetics and epigenomics.
4. Parkinson’s disease therapeutic strategies
Container Store (Gary Miller, better packaging for dopamine could avoid stress to neurons).
Anti-inflammatory (Malu Tansey, anti-TNF decoy can pass blood-brain barrier).
5. Personal genomics/exome sequencing
Rare disease diagnosis featured in the New Yorker. Threepart series on patient with GRIN2A mutation.
6. Neurosurgeons, like Emory’s Robert Gross and Costas Hadjpanayis, do amazing things
7. Fun vs no fun
Fun = writing about Omar from The Wire in the context of drug discovery.
No fun (but deeply moving) = talking with patients fighting glioblastoma.
8. The hypersomnia field is waking up
Our Web expert tells me this was Lab Land’s most widely read post last year.
9. Fine-tuning approaches to cancer
Image guided cancer surgery (Shuming Nie/David Kooby). Cancer immunotherapy chimera (Jacques Galipeau). Fine tuning old school chemo drug cisplatin (Paul Doetsch)
10. Tie between fructose effects on adolescent brain (Constance Harrell/Gretchen Neigh) and flu immunology (embrace the unfamiliar! Ali Ellebedy/Rafi Ahmed)
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Cancer immunotherapy, meet chimera

697px-Chimera_d'arezzo,_fi,_03

In Greek mythology, the chimera was a monstrous fire-breathing creature composed of the parts of three animals: a lion, a snake and a goat.

Adoptive cell transfer is advancing as a cancer immunotherapy technique. It involves removing some of a patient’s immune cells, culturing them in the laboratory, and then infusing the cells back into the patient. The idea is to enhance the ability of the immune cells to attack the tumors far beyond what the immune system was able of doing on its own.

Two promising examples are the National Cancer Institute’s approach of treating advanced melanoma with IL-2-stimulated immune cells, and several investigators’ approach of genetically engineering T cells to attack leukemias or lymphomas.

Jacques Galipeau and colleagues at Winship Cancer Institute have developed a chimeric molecule for stimulating immune cells, which appears to have unique powers beyond simply the sum of its two parts. The molecule is called GIFT4, a fusion of the immune signaling molecules GM-CSF (often used in cancer treatment) and IL-4.

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