By Akash Patel, Outreach Manager and Writer, Science Entrepreneur Club
Over the past few decades, there has been a new wave of cancer therapeutics, called immunotherapies, that are capable of activating the immune system to recognise and fight malignant cells. One of the emerging therapies of this type, which begins to enter the clinic, is the Chimeric Antigen Receptor (CAR) T-cell therapy. Here we explore CAR T-cell therapy and Autolus, one of the pioneering companies in the field.
When cancer occurs, a patient’s T cells are unable to recognise the presence of the malignant (cancer) cells. T cells are a type of white blood cell that form a part of the cell-mediated immune response. Cancer has the ability to inhibit the T cell response and evade the immune systems surveillance process - hiding in plain sight. The immune system contains a series of checkpoint proteins, some of which help to activate T cells in response to infection and others which put a ‘brake’ on the T cell response to prevent damage to healthy cells and tissues. Malignant cells are able to produce high levels of the checkpoint proteins (1) that inhibit T cell response and prevent them from attacking these cells. CAR T cells both attack the malignant cells and activate the T cells in the surrounding environment, thereby initiating an immune response against cancer. CAR T-cell technology, as a whole, generates activated T cells into the immune system that recognise some tumour surface proteins, called neoantigens.
Radio- and chemotherapies of the past have proven challenging for patients to undergo. These traditional forms of cancer therapies target malignancies, but in the process can also cause significant cell death and damage to surrounding tissue. On the other hand, CAR T cells have demonstrated real promise in enabling progression to a new era of cancer treatment. CAR T cells are a form of genetically engineered T cells that produce artificial T cell receptors.Their key advantage is their target specificity as the newly engineered T cell receptor can directly recognise neoantigens with little or no cross-target effects.
In 2014 Dr Martin Pule, senior researcher at the UCL Cancer Institute and leader of their CAR program, founded Autolus a clinical stage pharmaceutical company based in London, UK, that builds cell programming technologies. Stemming from Dr Pule’s research, Autolus has developed the next-generation of CAR T cells to tackle haematological and solid cancers with high clinical efficacy (2, 3). The company has grown from strength to strength in its first four years with an initial investment of £30m from Syncona and UCL Business (4). This was followed by a successful initial public offering (IPO) which raised $150m on the biotech-friendly NASDAQ stock exchange in June of 2018 (5). Autolus is in the process of expanding its manufacturing operations to the United States - a clear demonstration of their confidence in becoming a major player in the CAR T cell space. The unique aspects to their cell programming technology are proving successful at early trial stage and are the key driver to their current success.
The first target of Autolus’ technology is haematological malignancies, as is the case for fellow major CAR-T manufacturers, such as Kite pharma and Novartis (6, 7). This is because CARs can interact easily with B cells, a type of white blood cells, but have significant difficulty in penetrating solid tissue to tackle solid tissue cancers. However, Autolus’ products stand out from the likes of Novartis’ Kymriah and Kite’s Yescarta due to novel features such as the ability to modulate T-cell response in response to the occurrence of toxicities. They are striding forwards with clinical trials for several of their ‘AUTO’ clinical therapies and have recently released some promising results for AUTO1, which is designed to tackle Acute Lymphoblastic Leukaemia (8).
Autolus’ CAR T-cell technology is engineered precisely and specifically for the patient. Through a process known as leukapheresis, T cells are extracted from the patient’s blood following which a viral vector is added to transfer a gene that modifies the T cells to become CAR T cells. Following this process, the newly engineered CAR T cells are transferred back into the patient to target and destroy malignant cells.
The advantage of Autolus’ technology is the creation of various features for CARs that improve target specificity and prevent off-target events. They have developed an ‘advanced cell programming technology’ that enables modulation of T cell activity and an on/off mechanism to prevent and/or limit the likelihood of toxicity (2). A major issue surrounding the safety of CARs as a therapy is the engineered receptors’ ability to target non-tumour antigens in a phenomenon known as molecular mimicry. If the receptor binding site has a structure very similar to antigens on surrounding tissue, it can bind and cause toxicities (cross-reactions) that can prove lethal. The two most noted toxicities across the several generations of CARs are cytokine release syndrome (CRS) and neurotoxicities (9). Neurotoxicity is a prime example of cross-reaction in which antigens similar to those found in haematological cancers can be found in neural tissue (brain and nervous system). This toxicity has led to deaths, particularly when CARs have been administered to tackle solid tissue cancers. Cytokines are inflammatory proteins released as an immune response when CARs are administered. CRS is a systemic inflammatory response that has been observed with many antibody-based immunotherapies. It can prove uncontrollable and in several cases has resulted in patient death (10). Autolus has addressed this by providing an on/off switch for their CAR-T which either modulates the T cells’ activity or, in severe cases, eliminates the programmed T cells completely (2).
Autolus are gaining success at the clinical trial stage, with a recent presentation of initial data made on their phase 1/ phase 2 trial of their AUTO1 therapy at the American Association for Cancer Research meeting earlier this month. The trial, known as ALLCAR19, is investigating the efficacy of AUTO1 in acute lymphoblastic B cell leukaemia (B-ALL). There is currently only one approved CAR therapy for B-cell acute lymphoblastic leukaemia - Kymriah (4). AUTO1 therapy strives to compete for the market with its unique T cell modulation features. The therapy is able to bind to CD19 positive B-ALL cells, kill these cells and then disengage rapidly and in doing so reducing the likelihood of severe toxicities. The safety results demonstrated no patient suffered from severe cytokine release syndrome (CRS) and efficacy results showed “AUTO1 delivered promising early remission rates, CAR T cell expansion and persistence in this adult ALL trial cohort,” Dr Claire Roddie of the UCL Cancer Institute announced. The success can be summarised by two reported factors, the strong persistence of CAR T cells over a long period of time the low frequency of serious CRS events (6). The expansion of the CAR T cells refers to a continually increasing number of T cells activated to fight the cancer Furthermore, Autolus’ AUTO3 product has been provided with orphan drug status for Acute Lymphoblastic Leukaemia, as it is a rare disease, by the FDA (11).
Many challenges lie ahead for Autolus as they progress with phase 1/2 trials of their various CAR-T products. All drug development and clinical trials carry significant risk; as CAR-T is a fairly novel therapy, and with only two CAR-T products currently on the market, it is difficult to determine whether AUTO1 and AUTO3 will successfully achieve remission in patients. However, Autolus has made some promising progress to date with some positive news released regarding their AUTO1 trial. They have won investor confidence and have progressed successfully through both seed funding and IPO, providing them with the high levels of capital required to progress forwards with clinical trials. If nothing else, they demonstrate the opportunity and scalable impact of translating research out of the laboratory and into clinical products.