Clinical Research: Phase 1 - Phase 4

Beyond Boundaries: Revolutionary CAR-T Therapies Pave Way to Conquer Solid Tumors

Chimeric antigen receptor (CAR) T-cell therapy is becoming an increasingly important part of the cancer treatment landscape, with a growing number of clinical trials investigating its use across a range of cancer types. To date, the FDA has approved six CAR T-cell therapies, all for hematological malignancies and all primarily used as treatments for patients with advanced cancer who have exhausted other therapeutic options. Over the past five years, CAR T-cell research in hematological malignancies has increased, as have investigations of this novel therapy in solid tumors, which comprise the majority of cancers.

What limits the success of CAR-T applications in solid tumors?

  • Lack of solid tumor-specific target antigens. Many of the target antigens in solid tumors are also found in healthy tissues, leading to on-target, off-tumor toxicities. Moreover, studies have shown that, in some solid tumors, CAR-T-mediated targeting of a target antigen may result in downregulation of that target antigen, rendering the CAR-T therapy ineffective.1
  • Tumor heterogeneity. Solid tumors are often composed of different types of cells, which makes the task of identifying a suitable target antigen challenging. Tumor cell composition also varies among individuals with the same tumor type. Target antigen heterogeneity results in poor detection of cancer cells by CAR-Ts and leads to ineffective antitumor responses.
  • Immunosuppressive tumor microenvironment. Solid tumors have a complex microenvironment that may not only inhibit the activity of CAR-T cells, but also limit their ability to reach and infiltrate the tumor. Components of the microenvironment may also promote the development of resistance to CAR T-cell therapy.
  • Tumor targeting. Solid tumors can be bulky and diffuse, making it difficult to deliver a sufficient number of CAR T-cells to the tumor. In addition, poor accessibility of the target antigen by CAR T-cells leads to inefficient CAR-T stimulation, activation, and expansion. Further, the vasculature in solid tumors can be abnormal, making it difficult for CAR T-cells to reach the tumor. There is scientific evidence that tumor-applied mechanisms reduce secretion of vasculature-related factors, preventing CAR-Ts from crossing blood vessels and penetrating tumor tissue.2
  • Immune evasion. Cancer cells in solid tumors express inhibitory molecules that promote an immunosuppressive microenvironment, which makes it difficult for CAR T-cells to target them.
  • Safety. The side effects associated with CAR T-cell therapy, such as cytokine release syndrome and neurotoxicity, may be more difficult to manage in patients with solid tumors, especially if they are also receiving concurrent chemotherapy or radiation therapy.

But opportunities for CAR-T in solid tumors remain, and the research is growing

Successful development of CAR T-cell therapies for solid tumors requires a multidisciplinary approach that includes identification of solid tumor-specific target antigens, optimization of CAR administration and design, and conduct of preclinical studies and clinical trials.

Researchers have identified several antigens expressed on solid tumors which can potentially be targeted by CAR-T cells. These antigens include:

  • New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1)
  • Mucin-1 (MUC1)
  • Human epidermal growth factor receptor 2 (HER2)
  • Epidermal growth factor receptor (EGFR)

Researchers are developing next-generation CARs that can target multiple antigens on cancer cells to increase specificity. One approach under investigation for increasing CAR-T stimulation in solid tumors is the use of boosting vaccines to create an environment for CAR-T priming.3 Numerous variations in CAR-T engineering are also being studied to increase tumor infiltration rate. Recently, regional delivery of CAR-Ts has emerged as a strategy for enhancing antitumor activity in solid tumors.

Progress is also being made in exploring novel strategies for triggering or amplifying endogenous antitumor responses that help overcome the lack of definitive tumor-specific antigens and the limitation of poor tumor infiltration.3

Giving CARs a solid chance

In 2022, nearly one-third of CAR T-cell therapy clinical trials were focused on solid tumors.4 To date, preclinical studies have shown that CAR T-cells can effectively target and kill cancer cells in certain solid tumors, such as sarcoma, ovarian cancer and pancreatic cancer. In addition, several clinical trials are underway to evaluate the safety and efficacy of CAR T-cell therapy in solid tumors.

Table 1. A selection of CAR T-cell therapy trials in solid tumors5

Adapted from Kyte JA. Cancers. 2022;14(3):571.
CAR, chimeric antigen receptor; EGFR, epidermal growth factor receptor; FAP, Fibroblast activation protein; GPC3, glypican 3; MUC1, mucin 16; MUC16ecto, mucin 16 ectodomain; NECTIN4, nectin cell adhesion molecule 4; PSMA, prostate-specific membrane antigen.

CAR T-cell therapies are gaining prominence in cancer treatment, with many opportunities to expand access and applicability

While there is yet to be a CAR T-cell therapy approved for use in solid tumors, this is an intensive area of translational research. Several early phase clinical trials are evaluating the safety and efficacy of CAR T-cells, either as monotherapies or as part of combination regimens, in malignancies such as glioblastoma and gastrointestinal, renal, prostate, ovarian, and thoracic cancers. Though progress has been incremental, the next step in CAR-T evolution is approval for a solid tumor indication.

To learn more about current trends in CAR T-cell therapy research and development, view our on-demand webinar.

[1] O’Rourke DM, et al. A single does of peripherally infused EGFRvIII-directed CAR T-cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017;9:eaaa0984.

[2] Vedvyas Y, et al. Manufacturing and preclinical validation of CAR T-cells targeting ICAM-1 for advanced thyroid cancer therapy. Sci Rep. 2019;9:10634.

[3] Kozani PS, et al. Recent advances in solid tumor CAR T-cell therapy: Driving tumor cells from hero to zero? Front Immunol. 2022;13:795164.

[4] Data from Citeline Trialtrove®.

[5] Kyte JA. Strategies for improving the efficacy of CAR T-cells in solid cancers. Cancers. 2022;14(3):571.