By Bill Koski, Contributor
With 2018 in the books, we look back on another year of progress for immunotherapy. In December, the annual meeting of the American Society of Hematology (ASH) highlighted a flood of research for immunotherapies in blood cancers. Cell therapy leaders bluebird bio, Legend Biotech (a Genscript subsidiary), and Celgene all rolled out highly anticipated updates for their chimeric antigen receptor (CAR) T-cell therapies targeting BCMA in multiple myeloma. Regeneron captured investor attention with clinical data from a novel bispecific antibody that elicited a response in 10 patients treated with a type of relapsed lymphoma, and Autolus Therapeutics highlighted a unique bispecific CAR-T that showed promising results in leukemia and lymphoma. View all holdings of the Cancer Immunotherapy ETF (Nasdaq: CNCR).
Many of the blood cancers covered at ASH have served as testing grounds for new immunotherapies, with treatments finding early success and regulatory approvals in indications such as leukemia and lymphoma. For example, Novartis’ Kymriah, the first CAR-T therapy approved by the Food and Drug Administration (FDA), and Amgen’s Blincyto, the first approved bispecific antibody, both gained approval for treating types of leukemia. Similarly, Seattle Genetics’ Adcetris, the first FDA-approved antibody-drug conjugate, was first approved to treat Hodgkin’s lymphoma. The challenge today is whether some of these emerging technologies can be translated for uses beyond blood cancer and into broader types of cancer.
Now, with another ASH meeting behind us, we look at moving immunotherapies beyond blood cancer and into solid tumors, a type of cancer that originates in “solid” tissues like the breast, lung, or colon. Solid tumors like these can be more difficult to treat. Blood cancers have become a proving ground for new immunotherapies, in large part because the physiology of these “liquid tumors” can promote more favorable interactions between immune cells, signaling molecules, and tumor cells. While the checkpoint inhibition approach to immunotherapy has worked well in solid tumors, other hot topics, like CAR-T, bispecific antibodies, and antibody-drug conjugates, have faced more challenges in the clinic. This is because the harsh tumor microenvironment around solid tumors can suppress activity of the immune system. However, cancer researchers are hard at work to overcome the obstacles needed to see progress in this area.
In this research report, we focus on a novel emerging immunotherapy strategy, called T-cell receptor (TCR) therapy, which has some hypothetical advantages in treating solid tumors. TCR therapy shares many similarities with chimeric antigen receptor (CAR)-T therapy, and many tend to lump these two treatments together into a single therapeutic box. For this reason, we call it “the other cell therapy.” CAR-T and TCR therapy are both types of engineered cell therapy that seek to improve the ability of T-cells to target and kill cancer cells. In both treatments, a population of a patient’s T-cells (or alternatively, live cells from an allogeneic donor, as described in our research report, Allogeneic vs Autologous Cell Therapies), is isolated in the laboratory environment, engineered to express a protein receptor against a cancer target, and infused in a patient.
However, TCR therapy maintains several important differences from CAR-T therapy. The core difference is that CAR-T therapies can only see targets that are expressed on the outside of cancer cells. By contrast, TCRs allow immune cells to target fragments of a protein, called peptides, that are normally present inside of a cancerous cell, and would otherwise go undetected by the immune system. The incredible diversity of TCRs may enable new therapeutic inroads in targeting solid tumors that have been largely unresponsive to other types of immunotherapy. While there may be dozens of potential targets for CAR-T therapies, there may be hundreds for TCRs. We are therefore optimistic for the clinical potential of TCR- based therapy.
This review will take a deep dive into the world of the T-cell receptor. We review the basic concepts of immunology underlying T-cell immunotherapy, introduce the biological rationale for re-engineering the TCR, and discuss the clinical road ahead for this treatment avenue.
A Dive Into the Human Immune System
The immune system is one of the most complex systems in the human body. It is the first and last line of defense against numerous threats to our well-being, which include physical damage to our body’s tissues, pathogenic invaders like viruses and bacteria, and corrupt cancer cells. We will break down the layers of this complex system to look at the critical role that T-cells play in the immune environment, and introduce the rationale for utilizing these cells for cell therapy. Broadly speaking, the immune system can be divided into two categories: humoral and cellular immunity.
- Humoral immunity consists primarily of antibody molecules, which circulate in bodily fluids, historically referred to as “humors”, and bind to antigens that are present on pathogens like viruses, bacteria, and cancerous tumor cells. Our last report, Targeting BCMA: New Frontiers in Multiple Myeloma, discusses the role of the BCMA antigen in multiple myeloma, examines how antibody-secreting B-cells can go haywire, wreaking havoc on the humoral immune system in multiple myeloma.
- By contrast, cellular immunity is comprised of a myriad of cell types that work together, often in combination with the humoral immune system, to maintain a robust immune response. Cellular immunity can be further subdivided into the innate and adaptive arms. The innate response is an intrinsic defense mechanism where immune cells like natural killer cells and macrophages respond to known pathogens based on years of evolutionary pre-programming. In contrast to the innate immune system, adaptive immunity is acquired through exposure to different pathogens. For example, vaccines work by “teaching” the adaptive immune system to recognize and attack a pathogen, such as the flu virus. The core workforce of adaptive cellular immunity is composed of B-cells and T-cells. Today we focus on T-cells, as they are the main anti-cancer agents of the adaptive immune system. Three types of T-cells—regulatory T-cells (TReg), helper T-cells (TH), and cytotoxic T-cells (TC)— synergize to maintain an active immune response
Different approaches to immunotherapy introduce treatment strategies in different components of the immune system—antibodies augment humoral immunity, cancer vaccines engage antigen-presenting cells in the innate immune system, and CAR-T and TCR therapy seek to reprogram T-cells in the adaptive arm. This research report will focus on the adaptive arm of the cellular immune system, and specifically the important role that T-cells play in the immune environment.
Rationale for Reengineering T-cells
Broadly speaking, cytotoxic T-cells serve as cell-killing specialists. When healthy cells are infected by a virus, or when a normal cell develops a series of cancer-causing mutations, a normally functioning immune system will enable these cells to bind to and kill the aberrant cell. Often, the humoral immune system fails to mediate an adequate response to cellular malignancies because, on the surface, these cells look no different than healthy cells. What differentiates them is the activity that occurs inside of the cell. Because the vital organs of a cell are protected by a fatty shield called the plasma membrane, soluble antibodies are unable to bind to targets inside of the cell, rendering the humoral immune response ineffective.
Enter the T-cell receptor. Each T-cell contains a TCR against a unique target. What is special about the TCR is that it enables T-cells to identify aberrant cells based on intracellular targets—targets inside of the cell. The TCR binds to a protein complex called the major histocompatibility complex (MHC). The MHC is also called human leukocyte antigen, or HLA, in humans. For simplicity, we will refer to it only as MHC. Human cells constantly undergo a type of immune audit, where they break down a representative sample of proteins inside of the cell. Fragments of these proteins bind to MHC molecules, and the complex is displayed on the surface of cells for review by the immune system. This is like a fingerprint – it is how T-cells recognize a cell as being “you” as opposed to something that is foreign or mutated. In cases where the target is expressing something abnormal, interactions between cytotoxic T-cells and other immune cells such as helper T-cells and dendritic cells preferentially activate cytotoxic T-cells with TCRs against the aberrant target, causing cytotoxic T-cells with that specific receptor to grow and expand. When an activated T cell binds to a cancerous cell via the TCR, it will release a toxic chemical or activate a self-destruct signaling pathway to destroy the cancer cell.
With cancer, this is easier said than done. In many types of cancer, the immune system fails to mount an effective response against tumor cells. One reason this can happen is that naturally occurring TCRs may have only moderate or weak affinity for an MHC associated with a tumor-associated peptide in a cancer cell. Cancer cells often look similar to healthy cells, and immune cells are unable to distinguish between normal and diseased protein fragments. When this happens, helper T-cells will fail to effectively activate cytotoxic T-cells, and even when activated, the cells will be unable to bind to cancer cells.
This is what cancer researchers are trying to improve on today. Because of the natural ability of cytotoxic T-cells and helper T-cells to rally the adaptive immune system against cancer, immune T-cells offer a compelling gateway to cancer immunotherapy. Adoptive cell therapy is a type of immunotherapy that seeks to reprogram T-cells to more effectively detect and mobilize against cancer cells.
CAR-T vs TCR: Improving the Targeting Ability of T-cells
CAR-T and TCR therapy are both adoptive cell therapies that use a physician’s prior knowledge about the makeup of cancer cells in a specific patient to redirect immune T-cells against malignant cancer cells. The two therapies are very similar in concept. Both TCR and CAR-T redirect T-cells against a specified cellular target. In addition to conferring a targeting modality against a cellular target, both therapies use a similar manufacturing process that was described in detail in our article, Allogeneic vs Autologous Cell Therapies. As a brief reminder, blood is drawn from a patient and used to isolate helper T-cells and cytotoxic T-cells. A gene encoding the CAR or TCR is then inserted into the genome of this T-cell subset. The genetically modified T-cells are then expanded in the lab, and re-infused into the patient 2-3 weeks after the initial blood draw.
Despite these similarities, CAR-T and TCR differ in the way that the protein receptor is designed. A chimeric antigen receptor (CAR) replaces the TCR with a new receptor that utilizes a fragment of a human or mouse antibody to bind to targets outside of a cancer cell. The antibody fragment is linked to various signaling proteins inside of the T-cell that activates when the CAR binds to its target. The term “chimera” refers to the fact that the CAR is made from two or more different genes that are fused together to build out the receptor. Recall that human genes work like a code that specifies instructions for the manufacture of proteins. That is what allows T-cells to potentially identify cancerous cells—a cancer-causing genetic error will also result in an aberrant protein, which can be identified by the MHC and detected by the immune system. Thus, the CAR is made from a fusion of two or more genes.
By contrast, a TCR is based on the gene for the protein receptor that is already naturally present in T-cells. The gene for a desired TCR can be discovered in a single patient—for example, a patient that is able to mount an effective immune response against a type of cancer. This gene can then be introduced into other patients, or reengineered to improve the binding interaction with its MHC target. Sometimes, scientists may try to increase the strength with which a TCR binds to its target (called affinity). One process used to do this is affinity maturation. Affinity maturation starts by identifying a naturally occurring TCR with some ability to bind to a specific target. Thousands of small differences in the binding region of the TCR are randomly introduced to create variants of the original protein, and the subsequent variants are screened to identify a TCR with the ideal binding characteristics. The resulting product is called a “high-affinity TCR.”
The different receptor designs lead to different interactions between CAR/TCR and target cells. Antibodies, like the ones incorporated in CARs, evolved over many years to be able to bind to a diversity of targets. The TCR, on the other hand, evolved to specifically recognize subtle differences in the MHC. Thus, TCR therapy offers an exquisite sensitivity for the MHC complex that could allow detection of novel targets that might otherwise be undetected by a CAR, including novel antigens present in solid tumors.
One important limitation of TCR therapy is that there are differences in population genetics that affect the treatment’s tolerability. Different humans have slightly different versions of the MHC gene. The most common, HLA-A0201, is found in around 45% of Caucasians (according to research published in volume 127 of the journal Blood by Emma Morris and Hans Stauss). Because TCR binding is dependent upon recognition of the MHC protein complex, a unique TCR is required for patients with different MHC genetics. Most TCR therapies are being developed for HLA-A0201 genetics, so a different therapy would be required for patients with less common MHC genetics.
Finding the right target:
As with most immunotherapies, T-cell therapy relies heavily on identifying the “right” target. A compelling immunotherapy target will be:
- Present in high concentration in cancer cells and absent in healthy cells;
- Essential to cell-survival; and
- Present in a large patient population.
Many of the popular targets that we have discussed previously in the context of blood cancers, such as CD19 and BCMA, satisfy these conditions well. However, these antigens are unique to cancer development in blood cells. Compared with liquid tumors, solid tumors tend to be subtler, with a higher frequency of mutations occurring. This motivates a need for new, actionable targets in solid tumors.
New safety considerations:
Like other immunotherapies like CAR-T, TCR therapy carries with it the risk of over-activating the immune system, which can lead to dangerous and life-threatening complications like cytokine release syndrome and neurotoxicity. Although in many cases, physicians have learned to moderate these issues as they gain more experience with cellular therapies. Steroids or antibodies can be used to temper the immune system, attenuating the effects of cytokine release and neurotoxicity.
TCR therapy, because of the way that it targets protein fragments, introduces added potential for cross reactivity with healthy cells. Proteins in the body work much the same way as words in the dictionary. Proteins consist of amino acids. Like letters in a word, the unique sequence of amino acids can confer a substantially different meaning. When proteins are digested into peptide fragments to be displayed by the MHC, the same fragment can originate from different proteins. Consider the words “healthy” and “unhealthy.” Although the two words have drastically different meanings, the fragment “health” can be generated from both. The problem facing TCRs is that the protein will not discriminate between the “health” peptide that originated in “healthy” or “unhealthy” cells. Because there is no dictionary of all the peptides that can be generated by breaking down all the proteins in the human body, a TCR that is trained to attack one sequence which is present in cancerous blood cells might also recognize the same sequence that is generated from a completely different protein present in healthy heart cells, for example.
While several TCR therapies have been shown to be safe and tolerable, a few early TCR clinical trials have run into trouble with unexpected adverse effects in healthy tissues (an effect called on-target, off- tumor toxicity). High-affinity TCRs come with an added caveat. While increasing the affinity for a target on cancer cells can improve the efficacy of TCR therapy, it also introduces added potential for on- target, off-tumor toxicity.
Early Clinical Results Show Promise for TCR Therapy in Solid Tumors
TCR therapies first made a splash when Adaptimmune PLC announced results of a study of its NY-ESO TCR, which the U.S. Food and Drug Administration granted Breakthrough Therapy Designation for in February of 2016. In a type of solid tumor called soft tissue sarcoma, a cancer of the connective tissue, a TCR engineered to target NY-ESO induced partial tumor remissions in three of four patients treated. Glaxo Smith Kline later exercised an option to purchase exclusive global rights to the NY-ESO-1 TCR program from Adaptimmune, a transition which was completed in mid-2018. Dr. Hal Barron, who took over as Chief Scientific Officer and President at GSK in March 2018, said about the transition for the NY- ESO program:
“The data we’ve seen for GSK ‘794 point to the potentially transformational nature of this T-cell therapy, as this is the first cell therapy to show clinical response in solid tumors.”
While TCR data has been sparse since then, things heated back up at this year’s ASH conference in December. One of the most exciting new announcements from the meeting came from a study of KITE-439—a TCR targeting HPV16-E7—in 12 patients with different solid tumors caused by the human papilloma virus (HPV). HPV is a sexually transmitted virus that has been shown to cause cervical cancer, head/neck cancer, and several other types of solid tumors. KITE-439 is a human TCR that targets E7, a viral protein that is produced by cells infected with the HPV virus. All 12 patients on the study treated with KITE-439 saw a reduction in their tumor sizes at one point in the trial, with 6/12 patients achieving a partial response classified as at least a 30% reduction in tumor size. These patients had very advanced cancers, receiving up to 7 prior treatments. KITE-439 is under development by Kite Pharma, a Gilead subsidiary.
HPV-associated cancers are a unique case, but demonstrate an important proof-of-concept for TCR in solid tumors. There are a few reasons that the Kite study may become a standout. First, E7, the protein targeted by KITE-439, satisfies the conditions for a good immunotherapeutic target. E7 interferes with the activity of Rb, a “tumor suppressor” protein that is known to inhibit the formation of cancer and is therefore essential to tumor cell survival. Further, E7 is a viral protein and is not encoded by healthy human genes. E7 should therefore be present only in cells that have been corrupted by EBV. The protein E7 is also highly conserved across patients with EBV associated cancers, meaning that the protein is virtually identical in all patients with a cancerous or precancerous growth related to EBV.
The researchers in this study, led by Christian Hinrichs of the National Cancer Institute, also used a rather clever method to generate this specific TCR that poses several advantages. Instead of isolating the TCR from a patient that has already developed an HPV-associated cancer, the TCR was derived from an individual with intraepithelial neoplasia, an abnormal, precancerous growth that can potentially transform into cervical cancer. The study authors speculated that this approach was preferred because the immunosuppressive tumor environment in patients with fully-developed cancer would inhibit the ability of T-cells to enter the solid tumor environment, thus making discovery of an effective TCR difficult. In theory, a patient with intraepithelial neoplasia could mount a more active immune response against E7. An additional added benefit of using a human TCR without affinity modification is that it is unlikely to be cross-reactive. After all, the unmodified TCR was tolerated in the original host without off-target effects.
Beyond these two examples from Adaptimmune and Kite Pharma, however, clinical results with TCRs have not all been so positive. Adaptimmune published results in October at the European Society of Medical Oncology meeting from some of its other TCR programs targeting MAGE-A10 and MAGE-A4, two antigens that are found in various solid tumors including lung and ovarian cancer. Across both studies, the treatment failed to reduce tumor sizes, and many of the patients experienced severe adverse events. However, these were early studies and the company is still increasing the treatment dose so we will have to see if further data looks more positive.
Clinical Progress Awakens Commercial and Venture Interest in TCR Therapies
Still, excitement surrounding TCR therapy has launched a wave of early-stage clinical trials. The National Institute of Health (NIH) lists 152 results for active clinical trials under the keyword “TCR therapy.” We expect 2019 to be an enlightening year for TCR therapy as more of these ongoing trials report “first-in-human” results.
Business development and venture investment have helped further the TCR space lately. Bluebird bio inked expanded partnerships in 2018 with Medigene and Gritstone Oncology to build out a preclinical TCR portfolio and Kite Pharma also continued to solidify their TCR arsenal with two partnerships involving HiFiBio and Kiromic. In a notable move, Bahija Jallal, the former executive vice president of Astra Zeneca and president of Medimmune, announced at the start of the new year that she would be joining the TCR startup Immunocore as CEO. Immunocore is developing ImmTAC, a next-generation bispecific TCR. This executive move highlights the growing momentum of startups developing new TCR therapies.
The TCR buzz has also prompted an influx of funding in 2018 from venture capital, big pharma, and other private investors. Small companies focused on developing TCRs raised just shy of a billion dollars in 2018 through private placements, public offerings, and commercial partnerships. Venture funding has focused around four key technology areas relating to TCRs:
1) Traditional TCR therapies that target tumor associated or viral antigens in solid tumors. These include targets that we have discussed already, such as NY-ESO, MAGE, and E7.
2) TCRs that target novel “neoantigens,” a patient-specific disease target that occurs in mutated tumor cells. Neoantigens target somatic mutations, a type of mutation that is acquired after birth. In theory, because a neoantigen is acquired after birth, a cancer-related neoantigen should be present only in cancerous cells that were derived from the original cancerous cell with that somatic mutation. Neon Therapeutics and Gritstone Oncology, both of which went public in 2018, are developing TCR products targeting neoantigens.
3) TCR therapies that re-engineer the TCR to improve binding with a target. For example, the company TCR2 is developing a newly engineered TCR, called a TRuC-T cell, that allows a cytotoxic T-cell to engage more parts of the TCR to bind to a target independently of the MHC. TCR2 recently filed for a $100 million IPO after raising a $125 million Series B back in March of this year.
4) Technology platforms for identifying new TCR targets. Because there are so many potential viable targets in the wide world of TCRs, novel technology platforms intersect new bioinformatics tools with traditional biochemistry discovery techniques. In the first week of 2019, Genentech, a Roche subsidiary, inked a $300 million partnership with Seattle-based Adaptive Biotechnologies, with total potential payments exceeding $2 billion. Adaptive is an emerging leader in immunosequencing technology and under the new partnership, Genentech will have access to Adaptive’s T-cell discovery and immune profiling platform (TruTCR) to identify new neoantigen targets.
T-cell receptor therapy presents a promising avenue to engage the cellular immune system, and could open the door to a myriad of new therapeutic targets in solid tumors, However, this also carries with it new scientific and clinical challenges. New data in 2019 will help us learn where the field of TCRs is headed.
Opinions expressed are those of the author or Funds and are subject to change, are not intended to be a forecast of future events, a guarantee of future results, nor investment advice. Fund holdings and allocations are subject to change at any time and should not be considered a recommendation to buy or sell any security. Adaptive Biotechnologies, Amgen, Autolus Therapeutics, Cell Medica, Dendreon, Five Prime, Glaxo Smith Klein, Gristone Oncology, HiFiBio, Immunocore, Lion TCR, Medigene, Neon Therapeutics, Novartis, Sangamo, Tactiva Therapeutics, TCR2, Tmunity, Unum Therapeutics, and Zymeworks are not a holding of the Fund or affiliated with the Fund. Legend Biotech (a Genscript subsidiary is held by the China BioPharma ETF).