Adoptive cell therapy, also known as cellular immunotherapy, is a form of treatment that uses the cells of our immune system to eliminate cancer.
Some of these approaches involve taking our natural immune cells and simply expanding their numbers, whereas others involve genetically engineering our immune cells (via gene therapy) to enhance their cancer-fighting capabilities.
Our immune system is capable of recognizing and eliminating cells that have become infected or damaged as well as those that have become cancerous. In the case of cancer, immune cells known as killer T cells are particularly powerful against cancer, due to their ability to bind to markers on the surface of cancer cells known as antigens. Cellular immunotherapies take advantage of this natural ability in different ways.
- Tumor-Infiltrating Lymphocyte (TIL) Therapy
- Engineered T Cell Receptor (TCR) Therapy
- Chimeric Antigen Receptor (CAR) T Cell Therapy
- Natural Killer (NK) Cell Therapy
Today, cell therapies are constantly improving and providing new options to cancer patients. Cell therapies are currently being evaluated, both alone and in combination with other treatments, in a variety of cancer types in clinical trials.
Tumor-Infiltrating Lymphocyte (TIL) Therapy
Cancer patients have naturally occurring T cells that are often capable of targeting their cancer cells. Their existence alone, however, isn’t always enough to guarantee that they will be able to carry out their duties and eliminate their tumors. One potential roadblock is that these T cells must first become activated before they can effectively kill cancer cells. Another is that these T cells might not exist in sufficient numbers. One form of adoptive cell therapy that addresses these issues is called tumor-infiltrating lymphocyte (TIL) therapy. This approach harvests naturally occurring T cells that have already infiltrated patients’ tumors, and then activates and expands them. Then, large numbers of these activated T cells are re-infused into patients, where they can then seek out and destroy tumors.
Engineered TCR Therapy
Unfortunately, not all patients have T cells that have already recognized their tumors. Others patients might, but for a number of reasons activating and expanding them might not be sufficient to enable rejection of their tumors. For these patients, doctors may employ an approach known as engineered T cell receptor (TCR) therapy.
This approach also involves taking T cells from patients, but instead of just activating and expanding them, the T cells are also equipped with a new T cell receptor that enables them to target specific cancer antigens. By allowing doctors to choose an optimal target for each patient’s tumor, the treatment can be further personalized to individuals and, ideally, provide patients with greater hope for relief.
CAR T Cell Therapy
The previously mentioned TIL and TCR therapies can only target and eliminate cancer cells that present their antigens in a certain context (when the antigens are bound by the major histocompatibility complex, or MHC).
Recent advances in cell-based immunotherapy have enabled doctors to overcome this. Scientists equip a patient’s T cells with a synthetic receptor known as a CAR, which stands for chimeric antigen receptor.
A key advantage of CARs is their ability to bind to cancer cells even if their antigens aren’t presented on the surface via MHC. This renders more cancer cells vulnerable to their attacks. In October 2017, the U.S. Food and Drug Administration (FDA) approved the first CAR T cell therapy to treat adults with certain types of large B-cell lymphoma.
Given their power, CARs are being explored in a variety of strategies for many cancer types. One approach currently in clinical trials is using stem cells to create a limitless source of off-the-shelf CAR T cells. If successful, this could allow doctors to treat patients in a timelier fashion.
Natural Killer (NK) Cell Therapy
More recently, adoptive cell therapy strategies have begun to incorporate other immune cells, such as natural Killer (NK) cells. One application being explored in the clinic involves equipping these NK cells with cancer-targeting CARs.
There are currently two adoptive cell therapies that are approved by the FDA for the treatment of cancer.
CAR T Cell Therapy
- Axicabtagene ciloleucel (Yescarta®): a CD19-targeting CAR T cell immunotherapy; approved for subsets of patients with lymphoma
- Tisagenlecleucel (Kyrmriah®): a CD19-targeting CAR T cell immunotherapy; approved for subsets of patients with leukemia and lymphoma
Side effects can vary according to the type of adoptive cell immunotherapy—and what exactly it targets—and can also be influenced by the location and type of cancer as well as a patient’s overall health. In the case of cell therapies, these side effects can take the form of overactive immune responses and can lead to excessive inflammation via cytokine release syndrome (also known as cytokine storm), and can also cause neurotoxicity. These side effects can range from mild to moderate and can become deadly under certain circumstances. Fortunately, in most cases side effects can be safely managed as long as they are recognized and addressed early. Therefore, it’s extremely important that patients notify their care team as soon as possible about any unusual developments during or after treatment with immunotherapy. In addition, patients should always consult their doctors and the rest of their care team to gain a better and fuller understanding of the potential risks and side effects associated with specific adoptive cell immunotherapies.
The side effects most commonly associated with currently approved adoptive cell therapies are: acute kidney injury, bleeding episodes, cardiac arrhythmias, chills, constipation, cough, cytokine release syndrome (cytokine storm), decreased appetite, delirium, diarrhea, dizziness, edema, encephalopathy, fatigue, febrile neutropenia, fever, headache, hypogammaglobulinemia, hypotension, hypoxia, infections, nausea, neurotoxicity, pyrexia, tachycardia, tremors, and vomiting. Learn more on our immunotherapy side effects webpage.
Throughout its history, CRI has supported a variety of basic research aimed at improving our understanding of the identity and functions of our many immune cells as well as translational and clinical efforts that seek to use these insights in the development of cellular immunotherapies for cancer patients in the clinic.
Some of the most important contributions made by CRI scientists in the area of adoptive cell therapy include:
- In 1994-1995, CRI investigator Stanley Riddell, M.D., and CRI grantee Philip D. Greenberg, M.D., of the Fred Hutchinson Cancer Research Center, highlighted the importance of cytomegalovirus (CMV)-targeting T cells in protecting transplant recipients against infection, and showed that adoptive cell therapy could restore CMV-specific immunity in transplant recipients.
- In 2002, CRI grantee Cassian Yee, M.D., along with Stanley Riddell, M.D., and Philip D. Greenberg, M.D., all at the Fred Hutchinson Cancer Research Center at the time, demonstrated one of the first successful uses of adoptive cell therapy in melanoma with patient-derived immune cells.
- In 2003, CRI postdoctoral fellows E. John Wherry, Ph.D., and David Masopust, Ph.D., working in the Emory University lab of Rafi Ahmed, Ph.D., demonstrated the superior persistence and protective power of central memory T cells, and identified a receptor that was associated with these long-lived memory cells.
- In 2006, CRI postdoctoral fellow Yoshihiro Hayakawa, Ph.D., and Mark J. Smyth, Ph.D., of the Peter MacCallum Cancer Centre (Australia), revealed that Natural killer cells can protect against tumor formation through the NKG2D pathway.
- In 2014, CRI-SU2C Dream Team member Michel Sadelain, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center, showed that regional delivery of mesothelin-targeting CAR T cells improved their activity against cancer.
The following are some of the current CRI grantees whose research involves adoptive cell therapy:
- Hyungseok Seo, Ph.D.—a CRI-Donald J. Gogel Fellow in the University of California, San Diego (UCSD) lab of Anjana Rao, Ph.D.—is characterizing how certain factors influences cellular “exhaustion” in both T cells and Natural Killer (NK) cells, in order to identify targets that might be able to improve the effectiveness of adoptive cell therapies.
- Chun Chou, Ph.D.—a CRI postdoctoral fellow at Memorial Sloan Kettering Cancer Center—is evaluating the potential clinical value of recently-identified innate-like T cells (ILTCs), which could broaden our understanding of tumor-immune interactions and pave the way for novel adoptive cell therapies that utilize these cells.
- Jonggul Kim, Ph.D.—a CRI postdoctoral fellow at The University of Texas Southwestern Medical Center—is studying the microscopic clusters that form on the surfaces of T cells and are crucial for their activation. Better understanding of these clusters could lead to strategies to enhance the anti-cancer activity of the T cells used in adoptive cell therapy.
- Shivani Srivastava, Ph.D.—a CRI postdoctoral fellow in the Fred Hutchinson Cancer Research lab of Stanley R. Riddell, M.D.—is evaluating the effectiveness of CAR T cells in lung cancer, with the goal of identifying mechanisms that suppress their activity as well as combination strategies that might improve their effectiveness.
- Four CRI postdoctoral fellows at the University of California, San Francisco (UCSF) are working to improve adoptive cell therapy strategies. Rogelio Antonio Hernandez-Lopez, Ph.D., a CRI-Merck Fellow, is designing new T cell receptors that specifically attack only cancer cells that express high levels of the target protein. En Cai, Ph.D., a CRI-Robertson Foundation Fellow, is characterizing the process by which T cells search for and recognize antigens on the surface of cancer cells. Avishai Shemesh, Ph.D., working in the lab of Lewis L. Lanier, Ph.D., is developing a CAR for NK cells that enables them to achieve self-proliferation after they recognize tumor cells so they can carry out stronger attacks. Aileen W. Li, Ph.D., a CRI-Merck Fellow, is using a new technology involving artificial receptors to dissect which factors promote the growth or elimination of tumors.