First Patients Achieve Remission in Pioneering In Vivo CAR-T Cancer Therapy: A New Era of Off-the-Shelf Immunotherapy

In the field of cancer immunotherapy, although CAR-T therapy demonstrates significant efficacy, its high cost and lengthy manufacturing cycle have long been bottlenecks limiting its widespread application.

As reported by *Science* magazine, at the recent annual meeting of the American Society of Hematology (ASH), Kelonia Therapeutics announced encouraging clinical trial data:Four Multiple Myeloma Patients Achieved Remission Through In Vivo Generation of T Cells

This advancement, combined with another similar study previously published in The Lancet, heralds the promise of faster, more cost-effective “off-the-shelf” CAR-T therapies to break the current therapeutic impasse.

Chimeric antigen receptor T-cell (CAR-T) immunotherapy was named one of the "Top 10 Breakthroughs of 2013" by Science magazine and has become a standard treatment for various hematologic cancers. However, existing CAR-T therapies face significant challenges: they require extracting a patient’s T cells, transporting them to a laboratory, genetically engineering them using viral vectors, expanding them in culture, and then reinfusing them into the patient.

This process not onlyTime-consuming(usually requiring several weeks to a month), andExorbitant Costs(often reaching hundreds of thousands of dollars). For many patients with rapidly progressing disease, this one-month wait is often a matter of life and death; unfortunately, numerous patients pass away due to disease deterioration while awaiting cell manufacturing. Furthermore, to ensure successful expansion of the infused CAR-T cells, patients typically must undergo high-risk lymphodepleting chemotherapy prior to infusion to eliminate existing T cells, which further increases treatment-related toxicity and physiological burden.

To address these limitations, researchers have begun to explore ""In Vivo" Generation of CAR-T Cellsstrategy, which involves directly modifying T cells within the patient’s body. This approach promises to eliminate complex ex vivo manipulations and, by obviating the need for specialized ex vivo manufacturing facilities, significantly reduce both time and economic costs, making this life-saving therapy as readily available “off-the-shelf” as conventional drugs.

The core of the in vivo CAR-T strategy lies inUse of Genetically Modified Viral Vectors(such as lentiviruses), these vectors are meticulously engineered to display antibodies on their surface that specifically bind to T cells. Upon injection into the patient, they act like guided missiles, precisely locating and “locking onto” T cells within the complex blood environment. Once the virus attaches to a T cell, it enters the cell and releases its genetic payload—the CAR gene—thereby directly “programming” the generation of CAR-T cells capable of killing cancer cells in vivo.

At the ASH Annual Meeting, Kelonia Therapeutics presented its latest clinical data. This trial, conducted in Boston, enrolled four patients with refractory multiple myeloma, yielding encouraging results.

According to hematologist Joy Ho from Royal Prince Alfred Hospital, cancer cells were undetectable in the bone marrow of all four patients after one month of treatment, with one patient remaining cancer-free at the five-month follow-up. Compared with conventional CAR-T therapy, this trial demonstrated a superior safety profile and relatively mild side effects. Only three patients experienced mild cytokine release syndrome (CRS), which resolved rapidly after treatment, and no severe neurotoxicity was observed.

Prior to this, in July of this year, The Lancet also reported a similar study conducted by EsoBiotec and Shenzhen Puruijin Biotechnology. This study likewise enrolled four patients, all of whom achieved deep remission: abnormal cells in the bone marrow completely disappeared in two patients after three months of treatment, and were cleared in the other two after two months. Notably, the therapy also effectively eliminated extramedullary tumors in two patients, demonstrating its potential in treating refractory lesions.

However, the adverse effects observed in patients in this study were relatively severe. Some patients experienced sudden drops in blood pressure, hypoxia requiring oxygen therapy, and transient mental retardation and confusion. These findings also suggest that further research is needed on different vector designs and their safety profiles.

The results of these two trials are considered a significant step forward in the field of in vivo CAR-T therapy, providing preliminary proof of the feasibility of this approach. Pharmaceutical giants have also keenly recognized the opportunity; in March of this year, AstraZeneca acquired EsoBiotec, reflecting the industry’s confidence in this direction. It is for this reason that Yvonne Chen, an immunotherapy researcher at the University of California, Los Angeles, believes thatThe current question is no longer "whether it can be done," but rather "how high a level of efficacy and safety can be achieved."

Despite its promising prospects, this therapy still faces challenges. The primary concern lies inLong-term Safety of Lentiviral Vectors. Lentiviruses integrate genes into the host cell’s DNA, theoretically posing a risk of carcinogenesis. Therefore, Christian Buchholz from the Paul Ehrlich Institute emphasizes that patients must undergo close follow-up for several years to ensure no secondary tumors develop.

To mitigate this risk, companies such as Capstan Therapeutics (now acquired by AbbVie) are developing non-viral delivery systems based on lipid nanoparticles (LNPs). This technology, similar to that used in COVID-19 mRNA vaccines, employs tiny lipid particles to deliver CAR-encoding mRNA into T cells.

Unlike viral vectors, mRNA does not integrate into the genome and has a shorter expression duration within cells. This characteristic of "transient expression" may imply enhanced safety and a reduced risk of long-term side effects.

Although it remains to be seen whether in vivo CAR-T therapy can deliver long-term survival benefits comparable to those of conventional CAR-T therapy, it undoubtedly opens a promising new avenue for cancer treatment.