Novel Adoptive Cell Therapy Strategies for Advanced Solid Tumors

Cholangiocarcinoma (CCA) may be a prime target for immunotherapy, which can include bispecific antibodies, agonistic checkpoint antibodies, adoptive T-cell therapy (ACT), anti-programmed cell death-1 and/or anti-programmed cell death-ligand 1 therapy, or vaccines using antigens.¹

Findings from the phase 3, randomized, double-blind TOPAZ-1 trial established that immunotherapy and chemotherapy are the standards of care in patients with advanced CCA. This data showed a higher median overall survival of 12.8 months in the durvalumab group (durvalumab plus gemcitabine and cisplatin) versus 11.5 months in the placebo group (placebo plus gemcitabine and cisplatin).²

At the Cholangiocarcinoma Foundation 2024 Annual Conference, Dr Lesinski presented the history of ACT and novel ACT approaches that could increase survival in patients with CCA.

Throughout the 1970s and 1980s, donor lymphocyte infusions (DLIs) following bone marrow transplantation led to the development of ACT. DLIs from bone marrow donors were first utilized for the management of viral infections and relapsed leukemia.

However, there was a risk of graft-versus-host disease alongside DLIs, depending on the percentage of T cells in the product.³

Clinical remissions were observed with DLIs, especially in patients with chronic myelogenous leukemia. Interleukin (IL)-2 was first discovered in 1976, and in 1980, it was found to have the potential to generate lymphokine-activated killer (LAK) cells.^4-6

The first paper describing a complete response to LAK cells was published in 1985, and the following year, tumor-infiltrating lymphocytes (TILs) replaced LAK cells as a more effective method of ACT.⁷

Other advances in cell therapy have been made, including the finding that lymphodepletion, or the reduction in lymphocytes, enhances the persistence of ACT. Lymphodepletion is crucial in applying chimeric antigen receptor (CAR) therapy. It depletes and regulates natural lymphocytes, preparing the microenvironment to enhance CAR T-cell growth and longevity and decrease the tumor burden.⁸

Today, the field of ACT has expanded, especially from 2020 to 2022. Recent ACT approaches include tumor-associated and tumor-specific antigen-targeted T cells, TIL cells, natural killer/natural killer T cells, and CAR T cells at various stages, ranging from preclinical to phase 2 and 3 clinical trials.⁹

One ACT approach being investigated in patients with CCA is CAR T-cell therapy. This type of therapy removes blood from the patient to extract T cells. These cells are then used to make CAR T cells in the laboratory by inserting the gene for CAR into the T cells so that CAR is expressed on the surface of T cells.

Millions of these cells are grown and then infused back into the patient. CAR T cells then bind to the antigens on the surface of patients’ cancer cells, resulting in cell death.³

However, current ACTs have limitations, including antigen loss, limited persistence (ie, cell exhaustion and apoptosis), impaired trafficking to tumors, redundant mechanisms of immune suppression, and toxicity, including cytokine release syndrome and on-target/off-tumor toxicity.

Different mechanisms to circumvent these toxicities include employing a superior starting T-cell template, a more diverse antigen profile for targeting, engineering to resist exhaustion, and combining therapy.³

T cells can be used as a new engineering “template” to overcome ACT’s limitations.¹⁰

For example, CD26⁺CD4⁺ T cells were investigated as a template for T-cell engineering. These cells concurrently produce IL-17 interferon-gamma and other cytokines, such as IL-22, identifying them with a unique phenotypic property that helps eliminate tumor cells when redirected with the antigen.¹¹

PI3K inhibition with duvelisib is also being investigated for better T-cell propagation. Inhibition with PI3K increases the mitochondrial membrane potential and the expression of CD26 on the surface of the T cells.¹²

Other promising ACT approaches include TILs, T-cell receptor (TCR) cells, central memory T cells, and virus-specific T cells.¹³

Additionally, murine models have been used to further research ACT in CCA. These models have been used to study and characterize tumors and understand the immune landscape of CCA. This research has identified CD4 cells that express CD26, a molecule that marks T cells. Their goal is to create innovative animal models to reintroduce these cells and achieve effectiveness, aiming to increase the number of survivors of CCA through subsequent trials.

ACT approaches for CCA are still in the preliminary stages of development yet show potential as a future treatment option. These approaches include CAR T-cell therapy, TCR-based therapy, TIL approaches, and the use of other cell products, including natural killer cells and dendritic cells or combinations of these therapies.³

References

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