Is It Time for CAR T-cell Therapies in Solid Tumors?

Do CAR T-cell Therapies Offer Hope for Solid Tumors?

Revolutionizing hematological cancer treatment, chimeric antigen receptor (CAR) T-cell therapyhas proven effective in blood cancers. Treatment for 6 hematological malignancies is currently approved by the United States Food and Drug Administration (FDA), with 6 different CAR T-cell products available.

However, solid tumors, arising in organs and tissues have shown limited responses and slower progress. No CAR T-cell therapy for solid tumors is currently approved in the United States or elsewhere.

Why Are CAR T Cells Less Effective Against Solid Tumors?

Perhaps the greatest challenge is selectively targeting specific cancer-cell structures and eliminating the cells without harming healthy tissue. Hinrichs and colleagues highlighted this in November 2024 in JAMA in a review.

CAR T cells consist of "T cells genetically engineered to express a synthetic receptor recognizing a protein on the tumor-cell surface". Identifying surface antigens unique to tumors is difficult, however, so treatment may affect both malignant and healthy tissues.

This makes targeting and killing all tumor cells without harming healthy cells difficult.

Other barriers include penetrating dense extracellular matrix and overcoming suppressive cells and molecules in the tumor microenvironment that hinder therapeutic activity.

Promising Results Despite Slow Progress

Despite the challenges and slow progress, promising results with CAR T-cell therapies in solid tumors have begun to emerge.

• For example, in April 2023, NEJMpublished a phase 1-2 study in heavily pretreated children with neuroblastoma. An overall response occurred in 63% (17 of 27 patients) receiving an investigational CAR T-cell treatment, GD2-CART01 .
• In April 2024, Naturepublished another phase 1 trial in which 38 of 98 patients with gastrointestinal cancer responded to investigational Claudin18.2-targeted CAR T cells, a 39% rate. Responses were generally brief, however, and might have been related to chemotherapy given before infusion.
• In June 20242, another phase 1 study presented at ASCOfound objective responses in 12 of 24 patients with advanced hepatocellular carcinoma receiving GPC3-targeted CAR T cells (50%), while disease control approached 91% overall.

Other Cell-based Therapies Also Offer Hope in Solid Tumors

Beyond CAR T cells, other cellular approaches are promising, including two recently FDA-approved T-cell therapies:

• In February 2024, the FDA approved tumor-infiltrating lymphocyte (TIL) therapy for advanced melanoma: lifileucel (Amtagvi)was the product.
• In August 2024, it approved T-cell receptor (TCR) therapy for advanced synovial sarcoma: afamitresgene autoleucel was the treatment.

Response rates with these therapies are approximately 30%, with clear evidence of lasting responses in some patients. This is encouraging for previously treated patients with few alternatives.

Many cellular agents are being tested in early solid-tumor trials.

Hinrichs and colleagues previously reported, in a phase 2 trial, TIL activity in HPV-related cancers , including cervical, oropharyngeal, and anal cancers.

• Responses occurred in 5 of 18 cervical cancer patients and 2 of 11 patients with other HPV-related cancers.
• 2 cervical cancer patients had complete responses lasting years after a single cell infusion.

Hinrichs also reported, in a phase 1 trial, tumor responses in 6 of 12 patients receiving genetically engineered TCR T cells targeting HPV E7.

Of 8 patients resistant to checkpoint inhibitor immunotherapy, 4 also responded.

At Rutgers Cancer Institute, a phase 2 clinical trial is currently underway. An early-stage study is also testing a new TCR T-cell therapy targeting Kita-Kyushu Lung Cancer Antigen-1 in metastatic gastric, lung, breast, and cervical cancers.

Conclusion: What Is Needed for Success in Solid Tumors?

Despite encouraging findings, new strategies are needed for CAR T cells and other cellular therapies to succeed in solid tumors.

We need more treatments targeting antigens present on most or all tumor cells but absent from essential healthy tissues.

Improving therapeutic cell activity and developing more precise antigen targeting to distinguish tumors from healthy tissue will also be important.