Isharpal Singh, MS

Programming T Cells to kill Tumor Cells

Surgery, chemotherapy, and radiation therapy have been considered as the cornerstones of cancer therapy for years. But with the advent of targeted therapies like Imatinib (Gleevec®) and Trastuzumab (Herceptin®) there has been a considerable shift in the standard treatments for a number of cancers over the last decade. This is because these drugs tend to target cancer cells based on certain specific molecular changes.

This has led to a growing excitement in the field of immunotherapy which aims to harness the power of the patient’s immune system to combat the disease. An approach called as ACT (adoptive cell transfer) or Adoptive Immunotherapy based upon engineering patient’s own immune cells to recognize and attack the tumors has given cause for optimism in the broader clinical applicability of this approach[3].

A Living Drug

CAR-T Cell therapy acts as Living Drug by using genetically engineered T cells which produce special receptors on their surface called Chimeric Antigen Receptors (CARs). These receptors allow the T cells to recognize a specific antigen on tumor cells thereby avoiding the requirement of antigen processing and presentation by the target cell. Thus permitting the use of a single receptor construct specific for any given antigen in all patients. These genetically engineered CAR T cells are propagated under laboratory conditions until they number in billions.

These CARs consists of an extracellular TAA-specific single-chain antibody variable fragment (scFv), a molecular hinge region, transmembrane domains, and intracellular signaling domains. The function of Single-chain antibody variable fragment is to target tumor antigens in non-MHC-restricted manner while the transmembrane domains participate in dimerization of CARs and activation of T cells.

How it works?

T cells are considered as the workhorses of our immune system as these recognize and attack the invading disease cells. But in some diseases like Acute Lymphoblastic Leukemia (ALL) and Chronic lymphocytic leukemia (CLL) etc. B cells which are also found in the immune system become cancerous and tend to evade detection by T cells. To solve this problem T cells are collected from a patient followed reengineering in a lab to recognize and attach to a protein which is found only on the surface of B cells. These genetically reorganized cells are called chimeric antigen receptor T cells. These cells are then put back into the patient where they diffuse to find cancerous B cells. Since these reengineered cells multiply in the body, they home in on cancerous B cells and attack them as they would any commonplace infection. Moreover these cells remain in the body long after to continue fighting any new cancerous B cells.

Example based on this system which is currently in Phase 2 clinical trial is Novartis’s CTL-109 which uses T cells engineered to target the CD19 antigen present on the surface of nearly all B cells, both normal and cancerous. The data obtained from its 24-patient Phase II study on chronic lymphocytic leukemia presented at ASH (American Society of Hematology) meeting showed a 42% response rate. Thus successfully inducing a complete response among half of those subjects. Moreover a 68% rate of overall survival was obtained in the 9 month follow-up of this study [2].

The Future

The immense potential & promise of this technology has brought a no. of contenders to the table including big pharmaceutical companies like Novartis, Pfizer, Celgene, bluebird bio and others which are working to create next generation of programmed T-cells cells via T-cell engineering which can act as autonomous agents to kill tumor. Investors are also showing tremendous interest in this field which once consisted of a handful of academic medical centers. This is attributed to the benefits that this technology provides like MHC-unrestricted ability, active transfer into the tumor sites, in vivo development and lasting persistence over conventional therapies [1]. Without a doubt, CAR-based technology has been considered as the major step forward towards off-the-shelf cellular therapy.

But the results observed so far in the clinical trials have been modest due to the cytokine release syndrome (CRS), a bodily response to cell therapy that results in flu-like symptoms and in some cases even death. However, as we learn more about the cellular processes and the underlying mechanisms responsible for immune activation and memory the CAR-modified T cells will most likely be able to play an increasing role in developing a multidisciplinary approach towards these diseases by providing a cure for the established cancers (the ultimate goal of the field).

References

1. Cheadle EJ, Sheard V (2012). Chimeric antigen receptors for T-cell based therapy. Methods Mol Biol.2012; 907:645-66.
2. Maude SL, Teachey DT, Porter DL, and Grupp SA (2015). Blood 125(26): 4017-4023. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia.

3. Almåsbak H,   Aarvak T and  Vemuri  MC (2016). J Immunol Res. 5474602. CAR T Cell Therapy: A Game Changer in Cancer Treatment.

4. research community are calling the “fifth pillar” of cancer treatment.
5. One approach to immunotherapy involves engineering patients’ own immune cells to recognize and attack their tumors. And although this approach, called adoptive cell transfer (ACT), has been restricted to clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer.