Revolutionising Cancer Therapies
The possibility of using immune competent T cells for curing various human ailments has intrigued scientists and physicians for a long time. From developing universal Chimeric antigen receptor (CAR) T-cell therapy that make treatments more efficient to using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology for precise gene editing, these breakthroughs promise to elevate the effectiveness of cancer therapies.
By Dr GAURAV KHARYA
In 1989, Israeli immunologist Dr Zelig Eshhar reported the “Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity.” Subsequently, in 1991, Eshhar reported “Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors.”
However, these initial reports faced challenges as the structure lacked components to effectively activate and proliferate T cells in response to stimuli.
Evolution of CAR T-cell therapy
As our understanding of T cell functioning improved, it became clear that essential components needed to be added to enhance the functional potency of CAR T-cell therapy. This led to the development of the 1st generation CAR-T, with an antigen-binding domain connected by a hinge to a transmembrane domain (CD8/CD28), further connected to an intracellular signalling domain (CD3ζ).
While the 1st generation CAR-T significantly improved functionality, the desired anti-tumour effects were not fully observed, possibly due to poor downstream signalling or amplification.
To address these issues, a costimulatory domain, either CD28 or CD4-1BB, was added, resulting in the 2nd generation CAR-T.
Dr Zelig Eshhar reported the “Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity.” Subsequently, in 1991, Eshhar reported “Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors.”
Role of Viral Vectors in CART
An integral part of CART is the viral vector used to deliver the Chimeric Antigen Receptor (CAR) into T cells. Retroviral and lentiviral vectors, retaining viral integrating potential but lacking proliferation potential, have stood the test of time.
Using the 2nd generation CART construct and viral vectors, two products, YESCARTA by GILEAD for DLBCL and KYMRIAH by NOVARTIS for B cell ALL, have received FDA approval for clinical use.
Ongoing Developments
A 3rd generation CART, incorporating both co-stimulatory domains, is currently being tested. Beyond these advancements, scientists are exploring various combinations of CAR-T components to achieve optimal effects.
Globally, CAR T cell therapy has witnessed significant growth, with China leading in registered trials, followed by the USA and European countries. However, the use of viral vectors and patient-specific treatments comes at a considerable cost.
The average cost of available CAR T cell therapy ranges from 400,000 to 700,000 USD, posing challenges for countries like India and others with limited resources.
Specialised Nature and Limited Pursuit in India
Given the specialized nature of this field, requiring a blend of clinician-researchers and laboratory scientists, only a few groups in India are actively pursuing this concept.
Immunoact, a start-up from Society for Innovation & Entrepreneurship – SINE, IIT Bombay, began developing a second-generation mono-specific CAR in 2014, focusing on indigenous innovation. They initiated phase I Clinical Trials (CT) at Tata Memorial Hospital (TMH) Mumbai/Advanced Centre for Treatment, Research and Education in Cancer (ACTREC) in June 2021 and are now advancing to phase II CT, reporting positive safety results for their CAR. Simultaneously, Immuneel Therapeutics Pvt Ltd started phase II CT in June 2022, presenting initial findings at ASH 2022. The 2nd Gen mono-specific construct, previously used in Spain, is now under a tech-transfer agreement for phase II CT at Narayana Hrudayalaya Bangalore. Christian Medical College (CMC) Vellore uses a second-generation mono-specific CAR from Miltenyi Biotech for academic purposes, previously used in phase I CT at CMC Vellore. Both Immuneel and CMC Vellore face challenges due to the non-indigenous nature of their CAR constructs, which may impact affordability post-initial clinical trials.
Cellogen Therapeutics Pvt Ltd, a Delhi-based Cell & Gene Therapy start-up, is working on bi-specific 3rd generation CAR constructs to address challenges of antigen loss and limited in-vivo persistence. After completing in-vitro and in-vivo validations, Cellogen Therapeutics plans to initiate phase I CT by mid-2023. Challenges to be addressed include poor amplification, poor persistence, antigen escape, and affordability, with a primary focus on making the therapy effective and economically accessible. Overcoming these challenges hinges on indigenous development and innovative Despite the emphasis on cost-effectiveness, it’s crucial not to compromise on the quality of emerging therapies.
The average cost of available CAR T cell therapy ranges from 400,000 to 700,000 USD, posing challenges for countries like India and others with limited resources.
The Quest for a Universal Solution
Looking ahead to the future of CAR therapies, current developments relying on viral vectors and patient-specific approaches incur substantial costs. A potential solution is the vision of a ready-to-use UNIVERSAL CAR, where Chimeric Antigen Receptor T cells are manufactured using third-party T cells modified to lack TCR and MHC. This approach addresses both Graft-versus-Host Disease (GvHD) and CAR rejection, significantly reducing costs and enabling off-the-shelf use.
Precision Gene Editing with CRISPR
Another interesting approach involves using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology for CART manufacturing. CRISPR, a potent gene-editing tool, has been studied for targeting and repairing defective gene sequences linked to monogenic disorders. CRISPR offers the dual advantage of independence from viral vectors, decreasing production costs, and eliminating the risk of insertional mutagenesis. Precision in knocking down the TCR locus and introducing the CAR construct into the T cell is a key advantage of CRISPR.
Expanding the Horizon Beyond B Cell Malignancies
While current Chimeric Antigen Receptor (CAR)-T cell therapy use is mainly limited to B cell malignancies, ongoing research is actively addressing challenges to develop effective CAR therapies for solid tumours. This transformative potential indicates a promising future for advancing CAR therapies beyond their current applications.
(The author is the Clinical Lead at the Centre for Bone Marrow Transplant & Cellular Therapy and a Senior Consultant in Paediatric Haematology Oncology & Immunology at Indraprastha Apollo Hospital, New Delhi.)