In terms of sheer wizardry, the T-cell therapy technically deserves the prize. In order to “vanish” or cure the cancer, usually certain types of blood cancer, the treatment involves removing the T cells (cells in the bone marrow which are part of the immune system), white blood cells that fight viruses, from the patient’s blood and genetically engineering them to fight the cancer and then infusing the modified cells into the patient’s blood circulation. The therapy technically is so efficient that the T cells remain constantly vigil even though the cancer is gone.
The complexity is mindboggling and so are the side effects of the treatment which need a range of strategies to deal with them. For instance, if the modified T cells are taught to recognise B cells (if the cancer involves the B cells which are the antibody-forming cells of the immune system) and destroy them, then even when the cancer is gone, the modified T cells will continue to be the sentinels and systematically destroy the good B cells. No cancer but no B cells remain as well. The cured patient would need immunoglobulin infusions for the rest of their lives.
Apart from the complexity of the treatment and the specific infrastructure needed, the therapy is expensive and so, in countries where the majority may not be able to afford it, it has yet to catch on. The glad tiding is that this therapy is now under way in Bengaluru, a first for the nation. Immuneel Therapeutics was founded in December 2018 with a purpose to accelerate development of advanced cell and gene therapies and provide those to patients in India keeping affordability in mind.
Its founders are Kiran Mazumdar-Shaw (founder and chairperson of Biocon), Dr Kush Parmar (founder of Boston-based 5AM Ventures) and Pulitzer Prize-winning cancer doctor and researcher Dr Siddhartha Mukherjee. On his last visit to the city to launch his latest book The Song of the Cell: An Exploration of Medicine and the New Human (2022), he had spoken about Immuneel, noting India’s first integrated state-of-the-art cell therapy R&D and manufacturing facility which is now fully functioning while building the ecosystem needed to build novel and innovative cell therapy assets.
It has been licensed for its programme, the Imaging and Epidemiology (IMAGINE) study, which, according to Dr Arun Anand, COO and board member, Immuneel Therapeutics, is India’s first Phase 2 multicentre CAR-T therapy trial for a CD19 CAR-T in 2022 indicated for B-cell malignancies. The early results were presented in December last year at the 64th American Society of Hematology Annual Meeting & Exposition (ASH) held at New Orleans, the US. “IMAGINE builds on excellent Phase 1 clinical data from Spain for Varnimcabtagene developed by Hospital Clinic Barcelona,” Dr Anand says. “The trial is active and recruiting at multiple centres in India.” The IMAGINE study is evaluating the safety and efficacy of Varnimcabtagene autoleucel (IMN [1] 003A), a novel CD19 directed Chimeric Antigen Receptor T (CAR-T) Cell Therapy for treatment of B-Cell malignancies, such as Acute Lymphoblastic Leukemia (B-ALL) and Non-Hodgkin’s Lymphoma (B-NHL).” Incidentally, India joined the CAR-T cell therapy space in 2021 with Tata Memorial and IIT starting a single site CD19 CAR-T Phase 1 academic trial.
Historical roadmap of T-Cell therapy
The recognition of T-cell as a medical tool: T cells can easily search, recognise, and kill cancer cells facilitated by a ‘guide’ which directs them to the tumors. These antibodies, which are proteins, emerged as a valuable scientific reach and medical tool. In 1975, the first monoclonal antibodies (mAbs) were developed. The first mAb to be used as a cancer therapeutic was developed in 1997. This therapeutic mAb Rituximab (Rituxan) was soon approved to treat certain types of lymphoma.
Importance of CAR-T cells: Rituximab paved the way for several other targeted cancer therapies. In 1987, the first chimeric antigen receptor (CAR) was created by Israeli immunologist Zelig Eshhar. However, the early trials were not successful, and indeed, the field slowed for two decades, and was resurrected in the late 2000s when the DNA coding for this receptor was implanted in T cells to create CAR-T cells which targeted tumors. Once it binds to the tumor cell, the CAR-T cells multiply and kill the tumor cells in the vicinity and persist in the body for years and serve as ‘guards’ to call in additional CAR-T cells as necessary to destroy stray tumor cells.
First clinical trial: In 2011, U-Penn initiated the first clinical trials in patients with chronic lymphocytic leukemia and children with B-cell acute lymphoblastic leukaemia (ALL). From 2012 onwards, stellar results were reported for CAR-T therapies in children and adults with B-cell acute lymphoblastic leukemia (ALL), with complete remissions in patients in terminal stage. This was transformative science!
Latest in therapy: In 2017, cancer patients found hope in the historic victory of the efforts of cancer researchers when on August 30, Tisagenlecleucel (Kymriah) was approved by the United States of America FDA for the treatment of children and young adults with acute lymphoblastic leukemia (ALL). Soon after, on October 18, 2017, FDA granted approval for Axicabtagene ciloleucel (Yescarta) for treating patients with relapsed/refractory diffuse large B-cell lymphoma (r/rDLBCL) and other rare large B-cell lymphomas. T cells are interesting, because they are the body’s natural mechanism designed to kill abnormal cells.
To summarise, since the first historic CAR-T approvals in 2017, six CAR-T cell therapies have achieved widespread approvals, including Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), Tecartus (brexucabtagene autoleucel), Breyanzi (lisocabtagene maraleucel), Abecma (idecabtagene vicleucel), and Carvykti (ciltacabtagene autoleucel).
But what exactly is CAR-T cell therapy?
Dr Anand says, “CAR-T cell therapy is an individualised cell-based technique that involves removing some of the patient’s own white blood cells, including T cells. The right type of cells is selected from this pool, and then used to make CAR-T cells. The collected T cells are genetically treated in the lab to produce special receptors called chimeric antigen receptors, or CARs. These CARs are like hooks, and allow the T cells to recognise an antigen (or marker) at the surface of cancer cells and activate the T cells’ ability to kill these cancer cells. The CAR-T cells are infused back into the patient’s body to identify and destroy certain cancers. This personalised immunotherapy is one of the most promising areas of cancer treatment.” Call it bespoke therapy or creating personal assassins.
Who can avail this treatment?
The FDA-approved below conditions for CAR-T cell therapy include those with: B-cell precursor acute lymphoblastic leukemia (ALL), in people up to 25 years of age; diffuse large B-cell lymphoma (DLBCL); primary mediastinal large B-cell lymphoma; large B-cell lymphoma transformed from follicular lymphoma; high grade B-cell lymphoma; aggressive B-cell lymphoma not otherwise specified (NOS); mantle cell lymphoma; follicular lymphoma and multiple myeloma.
The bottom line: The expense and commercial availability of the treatment
Although there are a few other players in India working in cell-therapy space, India does not have any commercialised CAR-T cell therapy available for patients. Immuneel, too, has not rolled out commercially. Dr Anand says, “Immuneel’s targeting to reducing the price to 1/4th the US prices in India. Currently the cost of the drug in the US is nearly $450,000-500,000. Since these are personalised therapies, it is a very expensive affair. Immuneel, through its programmes, is innovating on several elements of the manufacturing and delivery system to bring cutting edge global quality programmes with global data to Indian markets at a fraction of global prices. This will set the trend for the growth of the ecosystem in the country, that can further innovate, increase scale, increase efficiency, and bring down costs further.
Roadblocks
Globally, the CAR T treatment is known to have caused serious side effects in some patients like high fevers, comas, and dangerously low blood pressure, however, in most patients the alarming symptoms resolve. Also, strangely, some patients have shown resistance to the therapy or have relapsed. In the roadmap ahead, these are the factors that will be tackled and resolved hopefully.