CAR-T therapy has revolutionized cancer treatment after the breakthrough of CD19 targeted CAR-T cells in treating B cell malignancies. Beyond the hype, however, one must recognize the limitations of CAR-T therapy so to fully explore its potential in changing current cancer therapy modality. The major limitations of CD19 CAR-T therapy include target antigen escape, exhaustion of CAR-T cells in vivo, potential toxicities, and the regulatory burden and high cost.
Behind our BCJ Correspondence is the paradigm changing study, the 4SCAR2.0 trial. Since 2013, we have treated more than 800 acute B-ALL and B cell lymphoma patients using the 4SCAR design involving more than 40 major hospitals in China. Accumulated experiences point to the obvious treatment logistics, the long-lasting cancer targeting effects of CAR-T cells require persistent CAR-T cells in vivo, and a multiple antigen targeting strategy. The rationale is simple, as illustrated in the Figure: the initial infusion of CAR-T cells leads to rapid tumor eradication and expansion of CAR-T cells; then, CAR-T cells are exhausted and residual tumor cells gradually grow back.
This accounts for many and most of the CAR-T treated patients, who suffer relapses and CAR-T failure. It is obvious that a second infusion of the exhausted CAR-T cells, or infusion of a new type of targeted CAR-T cells, may overcome the tumor relapse. Of course, a third infusion of multi-targeted CAR-T cells further increase the likelihood of long term remission. This is the proposed CAR2.0 concept, easily said than done, because it requires low cost technical backup and flexible regulatory support.
Another important factor for CAR-T therapy is the immune status of the patient at the time of CAR-T treatment. Why most patients opt for CAR-T therapy only after they have failed all other treatments when their immune system has been exhausted due to chemotherapies along with increased tumor burden? Unfortunately, the current medical guideline is to practice existing treatments before approaching new trials. It is a long and costly process for CAR-T therapy to be approved by regulatory agencies, and the best and logical and obvious solution often will take many years to be accepted by the medical community.
Based on the above analysis, Dr. Eugene Zvonkov of National Research Center for Hematology in Moscow, evaluated the low toxicity and efficacy nature and affordability of the 4SCAR2.0 regimen, recommended enrollment of B cell lymphoma patients early in their disease course. The blood cells were collected before heavy chemotherapy courses to ensure good quality of T cells for the CAR-T preparation. The infusions included primary, booster, and a consolidation combination of CAR-T cells, targeting multiple tumor antigens. Importantly, the total cost for each CAR-T preparation is kept below $10,000 USD, an affordable cost for many patients. The results are obvious. In the reported 4 cases of B cell lymphomas, all of them achieved long term remission up to this date.
Thus, it is possible to obtain continued prolonged complete remission with CAR-T therapy for B cell lymphoma patients, if the treatment is properly managed and planned. Again, any good medical technology, if not affordable, has only limited impact in helping the majority of patient population.
Lung-Ji Chang, PhD
Professor and President
Shenzhen Geno-Immune Medical Institute