A 64-year-old school teacher walks into a clinical laboratory at Penn Medicine riddled with tumors. Twenty-eight days later, after receiving an injection of his own t-cells, the patient has no trace of cancer. What accounts for this miracle, detailed in the August 2011 issue of the New England Journal of Medicine? 

That would be T-Cell immunotherapy -- an emerging class of treatment that unlocks the body's innate ability to fight cancer. It could change our relationship with humanity's longstanding killer. It's also changing Philadelphia.

This groundbreaking technology made international headlines in December 2012 after Penn Medicine reported several near death patients, with no other treatment options, went into remission just weeks after receiving a single treatment of their Chimeric Antigen Receptor (CAR) immunotherapy developed for CD19, a blood cancer target. In some cases, these patients obtained full recovery without bone marrow transplants or other therapies.

The CD19 CAR data inspired Novartis, the Swiss multinational drug company, to partner with Penn Medicine on the $20 million construction of the Center for Advanced Cellular Therapies (CACT) slated for this fall (Flying Kite, December 18, 2012). The research and development facility will be the first in the world dedicated exclusively to adoptive T-cell immunotherapy treatment. Novartis is also funding future CAR studies and will help expedite the lengthy FDA approval process. 

Now another immunotherapy leader, Adaptimmune, is blooming in University City. The growing biotech company is making gains with Affinity Enhanced T-Cell Receptor (AETCR) immunotherapy. The U.K.-based Adaptimmune opened clinical headquarters in the University City Science Center Port Business Incubator in March 2011 (Flying Kite March 23, 2011). They hold an exclusive license to AETCR technology, which was developed at Weatherall Institute of Molecular Medicine at Oxford University in 1999.

As Penn Medicine gets closer to commercialization -- a process promising new development and hundreds, if not thousands of jobs -- Adaptimmune has entered a manufacturing agreement with Progenitor Cell Therapy in Allendale, New Jersey. They've also raised enough private investment to complete the next two years of  clinical research and development.

According to the National Cancer Institute, over 12.5 million Americans had histories of cancer as of January 1, 2009. With continued advances in T-cell immunotherapy, doctors may one day have a treatment option that doesn't destroy healthy tissues. Furthermore, immunotherapies have been successful where traditional treatment was ineffective or unlikely to succeed, indicating the potential for a "cure" for certain types of cancer. 

Philly's oncological legacy dates back to 1960 and the discovery of the Philadelphia Chromosome -- the first description of a genetic alteration associated with cancer -- by researchers from Penn Medicine and Fox Chase Cancer Center. To this day, Fox Chase, Penn Medicine and the Children's Hospital of Philadelphia (CHOP), continue to rank nationally in oncology, attracting patients from around the world.

In fact, the city's position as a leader in the field helped lure Adaptimmune. The company has worked with Penn Medicine, using the same facilities as the CD19 CAR research team, since 2005. They currently manufacture their treatment at Penn's Clinical Cell and Vaccine Production Facility. Additionally, Penn aided Adaptimmune in evaluating early stage clinical results.

"There are many groups in the United States investigating T-cell technology in the use of oncology," says Gwen Binder-Scholl, Executive Vice President of Adaptimmune. "The majority of those groups are academic groups. Their work is basically proof of concept for academic purposes. We have this industry-academic partnership." 

Although admittedly in the early stages, both Penn and Adaptimmune reported high clinical performance during the annual meeting of the American Society of Hematology (ASH) in Atlanta, Georgia on December 10, 2012. Penn saw tumor loss in nine of twelve advanced leukemia and lymphoma subjects, while Adaptimmune said nearly eighty percent of 13 advanced multiple melanoma (MM) patients had meaningful responses.

Cancer is far more prevalent than the diagnostic rate suggests -- most early stage cancers are eliminated by the immune system. In certain instances, however, malignant cells escape and grow into tumors. 

The immune system attacks perceived antigens, or substances foreign to the body. Harmful bacteria and viruses carry these markers on their surfaces. Because they're spun from healthy tissues, however, tumors generally produce antigens in low levels -- or "imperfect" antigens that also exist on some healthy cells -- making them difficult for T-cells to detect.

T-cell therapy, a subset immunotherapy, provides patients with T-cells that seek out specific antigens associated with certain cancers. The treatment dates back to the late 1800s, when doctors discovered tumors could be destroyed in some patients through exposure to certain bacteria. After losing ground to advances in radiology and chemotherapy, interest in T-cell therapy reemerged in the early 1950s, eventually leading to experiments with T-cell transplants. While this method demonstrated major muscle against cancer, it also proved risky, complicated and costly.

Adoptive T-cell therapy, an increasingly popular form, supplements a patient's immune system with engineered T-cells. Penn's CD19 CAR treatment does this by extracting the patient's T-cells and adding antibodies using deactivated HIV cells. Once returned to the patient, these cells seek out a surface protein called CD19, found in leukemia and lymphoma.

AETCR, by contrast, engineers nonnative T-cells by adding and selecting mutations in it's receptor -- the surface molecule capable of recognizing an antigen. This increases the receptor's sensitivity to low levels of antigenic HLA-peptides of NY-ESO-1 and LAGE-1 proteins, which are produced by a range of tumors. Copies of enhanced TCRs can treat a group of patients sharing that same tissue type. 

"These are two different approaches to get at the same problem," says Binder-Scholl. "Each has their advantages and disadvantages and both have quite a bit of potential."

The MM trials, which began just six months before the ASH report, provided the first AETCR results. The patients were given the treatment after bone marrow transplants. Considering the typical success rate for marrow transplants averages about 30 to 60 percent, major to full tumor loss for 77 percent of subjects is significant.  

"The main question is 'Are we seeing a better response rate than what you typically see [with therapy]?'" explains Binder-Scholl. "All of our patients had some response and the numbers are at the very top end of what you would expect from stem cell transplant alone. It's encouraging."

Unlike the CD19 CAR treatment, AETCR has only been administered to patients after a bone marrow transplant. Adaptimmune plans to conduct AETCR-exclusive tests on MM patients this year.  

Both treatments have drawbacks. The CD19 CAR-engineered cells also attack healthy b-cells, which produce antibodies. Clinical patients have received regular injections of gamma globulin--blood plasma proteins including antibodies--and may have to continue those for the rest of their lives. During treatment, the rapid loss of tumors triggers a violent immune response, known as tumor lysis syndrome, which includes extremely high fevers, nausea and dangerously low blood pressure. These symptoms disappear, with the cancer, in a few weeks.

According to Binder-Scholl, AETCR is gentler. Still, the treatment has yet to demonstrate the same ability to proliferate throughout the body (CD19 CAR altered T-Cells increased 1000-fold in some patients). While there are dominate tissue types for each ethnicity, a library of tissue-compatible AETCR treatments is required to treat the masses.

The absence of cancer isn't considered a full remission until five years have passed, and Penn's results are only two years old. There have been a few examples, in both studies, where patients grew new tumors carrying new antigens. These trials, moreover, are considered midpoint-interim -- the first phase. It can take as long as a decade to bring treatment to market. 

After experiencing initial success with their respective blood cancer trials, Penn and Adaptimmune will expand their clinical portfolio, and test several cancers (as well as HIV) this year. Adaptimmune is also involved in partnership discussions with undisclosed pharmaceutical companies and a biotech company. By the end of 2013, they expect to add four employees to their team of five and expand their offices at the Science Center to make room for new growth. 

"We do know our bodies are capable of recognizing and eliminating tumor cells on an ongoing basis," says Binder-Scholl. "What has shifted over the past year -- in a large part due to the CD19 CAR data -- been an awakening of awareness among pharmaceutical companies and biotech companies about the power of engineered T-cell therapy."

The University City Science Center has partnered with Flying Kite to showcase innovation in Greater Philadelphia through the "Inventing the Future" series.

DANA HENRY is Flying Kite's Innovation & Job News editor.