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The Cho Research Laboratory was established in 2006 with the principal goal of helping to actualize the enormous potential of immunotherapy against cancer.  The concept of using the immune system as a weapon against cancer is not new; its very recent introduction into clinical reality has fundamentally changed the way we think about and treat cancer.  Our daily efforts are energized and motivated by the desperate need to offer new hope for patients with cancer.  By introducing you to our laboratory, our goal is to share our sense of renewed confidence and optimism with you.

The immune system has an amazingly flexible and powerful capacity to recognize and eliminate a seemingly infinite array of foreign viruses and bacteria from the body.  Yet, at first glance, this same immune system seems strangely incompetent against cancer.  Years of effort to therapeutically orient the immune system against cancer met with occasional successes, but a simple question remained: why is the immune system so ineffective at protecting us from cancer cells? 

Decades of research have begun to answer this question: developing cancers deploy a number of mechanisms to evade, weaken and escape the immune system.  The reality is that the immune system is constantly working to thwart cancers.  Microscopic photographs of tumors will often reveal swarms of tumor-infiltrating lymphocytes (TIL), or immune cells making a valiant effort to invade and destroy cancer cells.  The problem is that, before they ever have a chance to work, TIL are insidiously deactivated by the very cancers they are targeting.  The body has natural mechanisms designed to prevent immune responses from becoming overly active; cancers have evolved to use those very same mechanisms to turn off immune responses.  Recent breakthroughs that overcome some of these mechanisms have ushered in the modern era of cancer immunotherapy, in which novel immune-boosting treatments have transformed the care and outlook for some patients with some types of cancers.

However, it is becoming clear that we are reaching a plateau in this first generation of modern cancer immunotherapy.  The next question to answer has become: what more can we do to get the immune system to work against more cancers, more effectively?

This question is the focal point of our research effort.  Since its inception in 2006, our laboratory has worked to develop new ways to broaden and strengthen cancer immunotherapy.  Our initial work examined the effects of cancer on the life cycle of an important family of immune cells called CD8+ T cells.  T cells are the backbone of immunity; they can recognize and remember nearly every possible virus or bacteria to which we have ever been exposed.  Over the course of their life cycle, CD8+ T cells begin life as naïve T cells each capable of recognizing a highly specific pattern of foreign protein that might exist on a foreign, invading cell.  If naïve T cells ever encounter their target, they quickly transform into an effector T cells that are capable of rapid proliferation and violent killing of their target.  Once that target is eliminated, effector T cells undergo a sacrificial process of self-elimination because the body no longer needs such large numbers of killer cells.  However, a small subset remains and transforms into memory T cells.  These fascinating cells are capable of near immortality, and survive in small numbers just in case their targets should ever return – this is the basis of immunity.  

 For decades, immunotherapy research focused on using large numbers of effector T cells as the primary weapon against cancer.  This was for a very good reason; effector T cells are the foot soldiers of the immune system, capable of rapidly recognizing and killing their targets.  A breakthrough came when it was discovered that large numbers of effector T cells could be isolated and expanded from TIL.  A form of treatment known as adoptive immunotherapy, in which these effector T cells are expanded and infused back into patients, can be dramatically effective.  However, adoptive immunotherapy has been hampered by its complexity and therapeutic inconsistency.

In our early work, our laboratory discovered that, whereas cancers are highly capable of blocking and suppressing the growth and function of naïve and effector T cells, memory T cells are uniquely resistant to cancer.  Even momentary exposure to tumors disrupts the ability of naïve T cells to become activated, and stimulates effector T cells to undergo premature suicide.  In contrast, the ability of memory T cells to survive and reactivate in response to stimulation is completely unaffected by exposure to cancer.

 

 

The life cycle of the T cell is completely changed by even momentary exposure to cancer.  The ability of naïve T cells to undergo expansion is blunted by cancer, and effector T cells undergo accelerated suicide in response to cancer.  In contrast, the ability of memory T cells to function is completely resistant to cancer.  (From Cho CS. Cancer Immunology. In: American College of Surgeons Surgery: Principles and Practice, New York, NY: WebMD, 2011.)

 

 

            



Based on this exciting observation, we conducted studies to compare the ability of traditional adoptive immunotherapy using effector T cells to an experimental version of adoptive immunotherapy using memory T cells.  What we observed was dramatic; memory T cells are far more effective at blocking the growth of cancers. 

 

 

Mice were injected with melanoma tumors and treated with tumor-specific effector T cells (left) or memory T cells (right).  Whereas tumors eventually grew exponentially after effector T cell therapy, tumor growth was durably suppressed after memory T cell therapy.




Whereas infusion of effector T cells resulted in a quick but short-lived anti-tumor immune response, infusion of memory T cells resulted in a durable immune response that actually strengthened over time.  Because of their unique ability to survive and persist for long periods of time, we found that adoptive immunotherapy using memory T cells not only prevented the growth of tumors, but led to long-term immunity against cancer recurrence. 

 

Microscopic photographs of tumors after no therapy (left), effector T cell therapy (middle) and memory T cell therapy (right).  In contrast to no therapy and effector T cell therapy, memory T cell therapy resulted in a powerful immune response inside tumors, characterized by the presence of large numbers of TIL (tumor-infiltrating lymphocytes).

 




Our current work is focused on turning these exciting observations into clinical reality.  One challenge that we are actively pursuing is the fact that, whereas large numbers of effector T cells can be isolated and expanded from TIL, memory T cells exist in very small quantities.  Very recent work in our laboratory has identified a source and method for expanding massive quantities of cancer-specific memory T cells; validation of this method in patients with cancer will be the focus of our future studies.  In addition, we are also very interested in designing combinatorial strategies for immunotherapy.  Our laboratory has demonstrated that the combination of adoptive immunotherapy with another type of immunotherapy known as checkpoint inhibition actually results in a surprising synergy that leads to a broad and flexible immunity to cancer recurrence.  We have also found that the immunotherapy can cooperate with traditional forms of treatment (such as radiation, tumor ablation, or surgery) in very surprisingly counterintuitive ways; understanding these interactions will be essential as we integrate immunotherapy more intimately into the care of patients with cancer.