Understanding CAR T-Cells

CAR T-Cells are genetically engineered immune cells designed to target and destroy cancer cells. By reprogramming a patient’s T cells to recognize specific cancer markers, these therapies offer highly personalized and effective treatment. CAR T cell therapies are revolutionizing cancer care by providing long-lasting remissions and hope for previously untreatable cancers.

Over the years, significant progress has been made in optimizing CAR designs, improving their efficacy and safety. However, certain critical challenges remain unaddressed. Issues such as antigen escape-mediated relapse, where cancer cells mutate to evade detection, and loss of CAR T cell persistence significantly impact treatment outcomes. These challenges result in therapy failure in approximately 50% of patients, underscoring the need for ongoing research and innovation to enhance durability, precision, and effectiveness. New advancements in dual-targeting CARs and strategies to improve T cell fitness are among the promising approaches being explored to overcome these barriers.

There are two major challenges faced by first and second-generation CAR T cell therapies:

CD19 Antigen Escape-Mediated Relapse

Between 10-25% in ALL and between 20-30% in DLBHNL show recurrence after CD19
CAR T therapy due to CD19 antigen loss. Source: Cellogen Therapeutics

1. Antigen-mediated relapse, where cancer cells evade detection by losing target antigens. Between 10-25% in Acute Lymphoblastic Leukemia (ALL) and between 20-30% in Diffuse Large B-Cell Lymphoma (DLBCL) show recurrence after CD19 CAR T therapy due to CD19 antigen loss.

2. Another 20-30% patients of ALL or DLBCL develop relapse due to Lack of persistence, as CAR T cells often fail to remain active long-term, limiting sustained remission and reducing overall treatment efficacy. CD19 CAR T cells have shown variable in vivo persistence. Most T cells become dysfunctional/exhausted after activation, which results in elimination of these cells from the system.

How Cellogen is trying to address these two challenges?
Cellogen started its work to address the two main challenges with existing monospecific 2nd generation CAR’s. The two main questions at the core of R & D were: First, Can simultaneous targeting of multiple Tumor Associated Antigens overcome the CD19 antigen escape based recurrence without compromising the anti-tumor activity and persistence? And second, can combination of various costimulatory domains increase anti-tumour activity and persistence of CAR T Cells?

With these two basic questions in mind, the team at Cellogen designed multiple CAR constructs using different permutations and combinations of antigen targeting domains (CD19, 20,& 22) and different costimulatory domains (CD28, 41BB, ICOS & OX40). Almost 50 different constructs were synthesized and thoroughly tested in-vitro. Based on the robust two best performing constructs were subsequently taken forward for animal studies to assess their safety and efficacy.

The animal studies further corroborated the previous findings and showed superior efficacy of 19-20 and 19-22 bispecific CAR constructs with dual costimulatory domains (in tumor cell kit, proliferation and persistence) as compared to existing CD19 targeting 2nd generation CAR’s. Riding on the success of the robust pre-clinical data, Cellogen is now looking forward to initiating first in-human phase I/II clinical trials soon (awaiting regulatory approvals).

Source:Nature Review | Clinical Oncology

Limitations of Traditional Cancer Treatments:

For decades, cancer therapy depended on chemotherapy, radiation, or surgery. However, these methods often fail in relapsed or refractory cancers, especially leukemias and lymphomas.

The Rise of CAR T-Cell Therapy:

In the early 2010s, CD19-directed CAR T-cell therapy emerged as a game-changer, showing remarkable efficacy in B-cell hematological malignancies.
CAR T-cell therapy is a form of adoptive cell therapy (ACT), where a patient’s own immune cells are genetically modified to recognize and destroy cancer cells

FDA Approval and Clinical Success:

Impressive clinical outcomes have led to FDA approval of CAR T-cell therapy for various B-cell malignancies.
Many patients experience complete remission and significantly improved long-term survival.

Challenges and Limitations:

Despite its success, CAR T-cell therapy faces challenges such as antigen escape mediated relapse, limited persistence of CAR T-cells and high treatment costs.

The Need for CAR T-Cell Therapy in India:

With India home to 17% of the world’s population and registering over 700,000 new cancer cases annually, the demand for innovative cancer treatments is critical.
Establishing CAR T-cell therapy in India could significantly enhance cancer care, boost research, and strengthen the country’s healthcare economy.

Time Line of CAR T-Cells

1993

First-generation CAR (CD3< )

2003

2nd generation CAR (CD28- CD3<)

2004

2nd generation CAR (4-1BB- CD3<)

2007

First IND for CD19 CAR

2011

4th generation CAR (TRUCKs)

2013

Demonstration of BCMA as a functional CAR target in myeloma (Preclinical)

2014

First in-human BCMA CAR T therapy clinical trial (NCI)

2017

FDA approval of CD19 CAR T therapy (Kymriah) for ALL

2017

Ide-cel (bb2121) granted Breakthrough-therapy designation award by FDA and PRIME by EHA

2017

FDA approval Of CD19 CAR T therapy (Yescarta) for NHL

2019

Cilta-cel (JNJ4528) granted Breakthrough-therapy designation award by FDA

2021

FDA approval of CD19 CAR T therapy (Liso-cel, Breyanzi) for NHL

2021

FDA approval Of Ide-cel (bb2121 ) for myeloma??