Tales of an immunotherapy investigator: Exhausted T cells might be responsible for stubborn lymphoma

August 23, 2018 | by Abe Rosenberg

Cutaneous T cell lymphoma | City of Hope Cutaneous T cell lymphoma: Cover image from Cancer Immunology Research
Why would a young up-and-coming physician/researcher devote her entire professional life to battling one of the rarest, most obscure forms of cancer?
Maybe it's the spy inside her.
“My dad was a spy, and I wanted to be one too!” said dermatologist Christiane Querfeld, M.D., Ph.D., director of the Cutaneous Lymphoma Program at City of Hope's Toni Stephenson Lymphoma Center.  She grew up in Germany (“The Berlin Wall was still up. We were stunned when it came down!”) where her father served as an intelligence agent for the city-state of Berlin.
Though her early cloak-and-dagger dreams didn't pan out, Querfeld has found an ideal place to indulge her inner spy. As a leading authority on cutaneous lymphoma (cancer of the infection-fighting white blood cells present in the skin), she channels her natural inquisitiveness, a powerful desire to discover what lurks beneath the surface and a dogged determination to “put all the pieces together, think it through and figure things out.”
And when she says “all the pieces,” she means it. Querfeld is a quadruple-threat, trained in dermatology, oncology, research and pathology, giving her unusually broad ability to diagnose and treat this mysterious disease.

Solving the Mystery

“Christiane is a gifted clinician, pathologist and investigator,” said Steven T. Rosen, M.D., City of Hope's provost and chief scientific officer. Rosen, the Irell & Manella Cancer Center Director’s Distinguished Chair and the Morgan & Helen Chu Director’s Chair of the Beckman Research Institute, trained and mentored Querfeld at Chicago's Northwestern University, then recruited her in 2014 to join City of Hope's new Hematologic Malignancies and Stem Cell Transplantation Institute.
Solving the mystery of cutaneous lymphoma is a challenge Querfeld takes personally. She's fiercely devoted to her patients, and very aware of the unique struggles they face.
“This is a very visible disease,” she said, “It's disfiguring. You walk around with it and people notice.”
Cutaneous T cell lymphoma (the most common form, also called CTCL) can start as a simple rash, mimicking a number of common, noncancerous skin conditions. Over a period of years, CTCL may grow to include patchy, scaly areas, lumps or bumps, thickened skin, pimples, nodules or plaques on the scalp, forehead or body. It all adds up to an emotional trauma that other cancer patients never deal with: You can't spot most people with leukemia, for example, just by looking at them.
And most CTCL patients will carry that trauma for a long time. The disease usually progresses slowly, so it's not unusual for patients to endure the disfigurements for decades. As many as 60,000 Americans currently live with cutaneous lymphoma, with another 2,000 cases diagnosed each year.

Finding Her Passion

Querfeld didn't immediately gravitate to this unusual niche, nor to medicine at all, for that matter. In high school she cared more about art history and traveling the world. But a course in biology ignited a fascination with research, and by the time she reached Northwestern, she found herself “working alongside top-notch experts in a multitude of specialties ... who all focused on treating cutaneous lymphoma.”
“Initially,” she said, “it was very challenging to understand [CTCL]. But now, I'm almost addicted to it!”
Her “addiction” is fed by the maddening complexity of CTCL and its highly individualized nature. There is no cure, no “one size fits all” treatment. The options — from skin-directed therapies like ultraviolet light therapy and topical steroids to “systemic” treatments like chemotherapy — must be custom-tailored to each case, with no reliable means of predicting the outcome. Because no two patients and no two immune systems are alike, two seemingly “identical” cases of CTCL may react differently to the same treatment.

Immunotherapy Provides an Answer

But what if researchers could unlock the key mechanism by which CTCL wreaks havoc with the immune system? It would be a major step toward wiping out this rare but stubborn disease through immunotherapy. That's the goal that drives Querfeld and her colleagues.
And that's why Querfeld is excited about the discoveries outlined in her new paper featured on the cover of Cancer Immunology Research, a publication of the American Association for Cancer Research.
The paper explains how, for the first time, Querfeld's team was able to study living T cells taken directly from cancerous skin samples, something never done successfully before (previous experiments relied on T cells harvested from blood or old cell lines, a less precise method.)
How did they do it?
Thirty-seven patients agreed to have some of their lesions shaved away under local anesthesia. Those skin fragments were placed in an incubator for 30 minutes so the layers (epidermis and dermis) could be separated. The newly-separated samples were then dropped into a special liquid cell culture for 36 hours.
What happened next must have brought a few smiles to the researchers' faces.
“We just let them float in that cell culture,” recalled Querfeld. “And we watched. And all the T cells crawled out of the tissue, so we could now analyze them!” Even better, because so little had been done to them chemically or physically, the T cells remained very close to their original, in situ (on site) condition, enabling a highly accurate analysis.
And that's when things got interesting.
Querfeld-Christiane Christiane Querfeld, M.D., Ph.D.

Tricks of the Trade

“It's fascinating how CTCL tricks us in order to survive,” said Querfeld. Careful analysis of those T cells revealed some of that trickery, described as “T cell exhaustion.”
In a healthy person, T cells lead the immune system's attack on any foreign invaders — an infection for example, or cancer. Those same T cells are reined in by “checkpoints” which prevent the immune response from going too far and damaging other parts of the body. Some cancers cleverly take advantage of those checkpoints to either “hide” from T cells or disrupt them. New drugs called checkpoint inhibitors outsmart those cancer cells and reactivate the T cells.
By examining her skin-derived  cells, Querfeld discovered how the T cell defense process has been rendered dysfunctional in cutaneous lymphoma. The T cells, having been constantly and repeatedly activated because of chronic inflammation typical in CTCL, have become overwhelmed, or “exhausted,” incapable of doing their job. Further, the team found that the more advanced the cancer, the greater the T cell exhaustion, until, in the later stages, the system is “totally out of balance.”
“These results,” the paper concludes, “justify identification of antigens driving T cell exhaustion and the evaluation of immune checkpoint inhibition to reverse T cell exhaustion earlier in the treatment of CTCL.”
“We confirmed,” added Querfeld, “that in CTCL, the cancerous T cells have been exhausted, and that they have a definite signature. This knowledge is going to get us closer to the right immunotherapies.”
What this means is that researchers may have found their clearest roadmap yet for developing drugs that may one day accomplish what no current treatment can do: properly harness the immune system to eliminate cutaneous lymphoma entirely.
Querfeld's trainer/mentor/recruiter is not a bit surprised.
“Dr. Querfeld's work is already having a profound benefit for her patients and rapidly advancing the field,” added Rosen, admiringly.
Of course, these findings, as significant as they may be, are just a preliminary step in what's certain to be a long, challenging path. That's just fine with the would-be spy who watched the Berlin Wall crumble. Tough challenges don't faze her. They energize her.
“I like doing things that are hard!” she said, smiling.
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Learn more about cutaneous lymphoma and our program. If you are looking for a second opinion about your diagnosis or consultation about your treatment, request an appointment online or contact us at 800-826-4673. Please visit Making Your First Appointment for more information.
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