Novel Cellular Therapy

Our team has been engaged in both clinical and laboratory research to understand how we might explore the natural laws of immunity in the fight against cancer, without genetic manipulations. In this process we have developed several novel forms of cellular therapy employing four distinct cell types — each branded as a proprietary protocol of our group.

AbaNI-15 is our proprietary Natural Killer (NK) cell therapy protocol developed by our team in 2022. NK cells are a unique population of lymphocytes (a type of strong and potent cell of the immune system) which are capable of defending us against both viral infections as well as cancers. They comprise about 5–10% of all the lymphocytes circulating in the peripheral blood.

Unlike T cells which comprise 60–70% of the lymphocytes, NK cells do not need to recognise each virus or each cancer cell by their respective signatures (antigens). Because of their very strong killing potential, they are kept under constant inhibitory control. Under specific circumstances, the NK cells get activated and kill the target cells which might be cancerous or infected with viruses, with a ferocity barely encountered in any other human cells. However, the NK cells are short lived (survive for about 2 weeks in the circulation) and have to be in a constant state of production to maintain the necessary protection for the human body.

Along with a few groups in the US and Europe, our group identified a unique population of NK cells which are strong killer cells but unlike the conventional NK cells survive in the circulation for a very long time (years). These cells are not naturally produced but develop when the body is faced with a particular virus called Cytomegalovirus (CMV). Almost 95% of the Indian population has been exposed to this virus and hence are naturally endowed with the capability of producing these strong, long-lived, killer NK cells (also known as Adaptive NK cells).

Our group has been working on these Adaptive NK cells with respect to Cancers and BMT as well as Covid-19 infection. While exploring Abatacept for prevention of GvHD in Haploidentical transplants, we discovered that abatacept not only has a sparing effect on NK cells but in-fact promotes the killer function of NK cells particularly the adaptive type. Following a series of lab experiments carried out over 5 years, exploring the effects of Abatacept and various cytokines on NK cells, we have developed a novel NK cell product called AbaNI-15.

On a compassionate use named patient program, AbaNI-15 has been used in 12 patients with refractory or resistant Acute Leukemia undergoing Haploidentical Transplantation. The early results are very encouraging. Unlike CAR-T cell therapy, this treatment has not been found to be associated with any major side effects.

This treatment is available at our institution under a compassionate use named patient program.

Bone marrow stem cells rest within a nest of other supportive cells, the primary component of which is mesenchymal stem cells or mesenchymal stromal cells (MSC). These cells have the unique ability of differentiating into other cell lineages such as osteoblasts (bone), chondrocytes (cartilage) and adipocytes (fat). Under certain conditions, these cells can also differentiate into various other cell lineages and due to this reason, they have been a special cell of interest in regenerative medicine. At the same time, MSCs also possess a unique immunosuppressive and immunomodulating property which have made them an attractive proposition for inflammatory conditions where the immune system is hyperactive.

One such condition in relation to BMT is the dreaded complication of severe GvHD. In patients who fail to respond to steroids and other therapies for severe GvHD, MSCs have often been found to be effective in reducing the severity of symptoms and at times result in complete remission of GvHD.

MSCs can be sourced from many tissues which include bone marrow, umbilical cord blood, placental tissue and adipose tissue. Our group has developed a distinctive process of manufacturing of MSC for treatment of GvHD sourced from bone marrow of multiple healthy donors. This proprietary product is named MAVIcel.

MAVIcel has been used on a compassionate named patient program in over 10 patients. This has been found to be highly effective in control of acute and chronic GvHD, with little or no side effects.

This product is currently being explored in an institutionally approved clinical study for patients with GvHD and inflammatory conditions.

T lymphocytes are the dominant immune cells in the human body which are extremely sophisticated weapons used against viruses or cancers as and when needed. They are very long lived cells whose production and functions are heavily regulated so that they do not attack normal cells or tissues in the body. This regulation is governed by a specific type of T cells called Regulatory T Cells (Treg) which control excess T cell activity in both health and disease.

GvHD, the most dreaded complication of Allogenic BMT, happens due to imbalance of the attacking T cells and the Tregs. While all the existing treatment of GvHD is geared towards controlling or eliminating the T cells which are attacking the patient's body, there is no effective therapy to restore the deficit of the Tregs. In addition, under situations of extreme inflammation, Tregs might lose their regulatory capability and turn rogue. This makes reliance on Tregs for controlling situations like GvHD less feasible. Unlike infusion of other cellular components like conventional T cells, NK cells or MSCs, infusion of Tregs has not been established in clinical practice despite its pivotal role in correcting the immune imbalance.

Our group has been working on identifying a stable population of Tregs which are less infidel in extremely stressful conditions. This particular subpopulation of Treg might be useful in patients with aggressive GvHD. Based on these findings, we have developed a cellular product named REGRAcel. Clinical exploration of this product is ongoing. We hope to initiate a clinical study in the near future.

ECP (Extracorporeal Photopheresis) dates back to ancient India and Egypt, where people with vitiligo ingested a plant (Ammi majus) found on the banks of the river, bathed in the sun, and noticed recovery in melanin production. Psoralen (8-methoxypsoralen [8-MOP]) is a photoreactive substance isolated from these plants.

ECP is defined as a technique of manipulating white blood cells (lymphocytes) outside the body in a way that, when they are re-infused to the patient, cause downregulation of lymphocytes (majorly T-lymphocyte activity) in patients. This process involves collection of mononuclear cells from the patient's blood, followed by addition of Psoralen and irradiation with UVA before reinfusion. As the irradiation is done outside the body, the risk of phototoxicity is negligible — however, it is recommended to use sunscreen and photoprotective sunglasses while on treatment.

This technique is employed in many conditions where the lymphocytes in the blood of an individual become hyperactive and cause excess inflammation. One such condition related to BMT is GvHD. ECP has been found to be successful in dampening the severity of GvHD in situations where it is non-responsive to standard drug-based therapies. This applies to both acute and chronic GvHD.

Approved Indications

• GvHD
• Cutaneous T Cell Lymphoma
• Solid organ transplant rejection
• Certain autoimmune diseases

How ECP Works — Current Hypotheses

How ECP tames the lymphocytes is not fully understood. There are several hypotheses which include:

• Inducing death in the hyperactive lymphocytes by upregulating proteins responsible for cell death.
• Transforming the partner cells of T cells (antigen presenting cells) to a more mellowed and non-reactive state.
• Increasing the number and function of Regulatory T Cells which are inherently poised to control hyperactive T cells.

The Procedure

ECP is not a one-off treatment for GvHD. Several such procedures (1–2 every week) are needed for several weeks or months. The collection of lymphocytes in the patient involves putting in a central line (particularly in children). The collected cells are then subjected to brief exposure to Psoralen and UVA therapy under sterile conditions and returned back to the patient as an IV infusion. The procedure is generally safe and no major side effects have been reported to date — apart from the inconvenience and side effects related to the central line and/or lymphopheresis procedure.

In addition, we are exploring novel approaches of combining other forms of cellular therapies with ECP in treatment of GvHD and other autoimmune disorders.