What is the magic of this cell therapy to make the tumors of patients with advanced lung cancer disappear completely?

Lung cancer is one of the leading causes of cancer deaths in the world, and about 85% of them are non-small cell lung cancer (NSCLC)

Recently, a study published in Nature Medicine showed that using lung cancer patients’ own immune cells as cell therapy may give some NSCLC patients who do not respond to PD-1 inhibitors a lasting remission

Tumor infiltrating lymphocyte therapy: expansion of "soldiers" fighting tumors

Tumor infiltrating lymphocytes (tumor infiltrating lymphocytes, TIL) are lymphocytes that leave the blood circulation and migrate to the vicinity of the tumor

However, there are too few TILs near many tumors, and their ability to kill cancer cells is inhibited by a variety of factors in the tumor microenvironment

Although TIL therapy has a significant effect on melanoma, it is not effective in treating other types of cancer

Brings sustained relief to patients with lung cancer who are ineffective with PD-1 inhibitors

In this study, researchers surgically removed tumor tissue from patients with advanced NSCLC, isolated TIL cells from it, and expanded them through IL-2 stimulation in vitro

The results of the test showed that among the 16 patients who received treatment, 11 patients experienced tumor shrinkage after one month of treatment.

"In this case, many patients have only a few weeks or months of life," said Dr.

▲The performance of patients receiving TIL therapy, the blue line and blue column are patients with complete remission (picture source: reference [2])

Advantages of TIL therapy

When it comes to cell therapy, we may first think of CAR-T cell therapy and T cell receptor (TCR) cell therapy

Compared with CAR-T and TCR cell therapy, the difference between TIL is that it does not require genetic engineering

In addition, because the cells used in TIL therapy are natural TIL cells that migrate into the tumor, researchers have not yet observed their off-target effects and the phenomenon of triggering cytokine release syndrome, which may avoid troubles CAR-T and TCR-T.

▲Comparison of TIL therapy with CAR-T, TCR-T cell therapy and immune checkpoint inhibitors (picture source: Iovance Biotherapeutics official website)

In this study, the analysis of TIL therapy also verified its ability to target multiple tumor-associated antigens

▲The TIL cells of a patient who achieved complete remission contained lymphocytes against multiple tumor-associated antigens, and were greatly expanded after being transfused into the patient's body (picture source: reference [2])

Multiple TIL R&D projects have entered the clinical trial stage

In June of this year, Iovance Biotherapeutics announced that the TIL therapy LN-145 developed by the company has also obtained positive preliminary results in clinical trials for the treatment of patients with metastatic NSCLC

A review article published recently pointed out that between 2011 and 2020, a total of 22 different TIL products were evaluated in 79 different clinical trials

▲Characteristics of TIL therapies evaluated in clinical trials (picture source: reference [6])

Challenges and future of TIL therapy

Although TIL therapy has made great progress in recent years, generating enough TIL cells is still a challenge for developers

Image source: Iovance Biotherapeutics official website

Another challenge that TIL therapies face is that the stability of the efficacy is difficult to assess, because they are produced by the expansion of TIL cells isolated from the patient’s tumor, and among these TIL cells, the only cells that can produce powerful killing effects on the tumor are For a small part of it, the proportion is difficult to estimate in advance, which leads to a large difference in the efficacy of TIL therapy between different patients

The strategy adopted by Dr.
Steven Rosenberg of the National Cancer Institute is to screen TIL cells, expand the T cells that recognize new antigens, and infuse them back into the patient
.
However, the addition of a screening process will extend the production time of the therapy
.

▲Two production strategies for TIL therapy, screening targeting tumor-associated antigens or not screening (picture source: reference [6])

At present, the development of next-generation TIL therapies aims to transform TIL cells through genetic engineering to improve their survival ability and anti-cancer activity
.
By introducing transgenes expressing IL-2 or IL-12 cytokines into TIL cells, the modified TIL cells may have longer persistence in the body
.

Another strategy is to use CRISPR gene editing technology to knock out proteins that inhibit T cell function
.
Last year, researchers at the University of Minnesota found that knocking out an immune checkpoint protein called CISH in TIL cells can increase the anti-cancer activity of T cells
.
They have launched a clinical trial to test the effectiveness of TIL cell therapy produced by this method in patients with gastrointestinal cancer
.

We expect that with the in-depth understanding of immuno-oncology and the advancement of innovative technology, TIL therapy can bring lasting relief to more types of cancer patients as soon as possible
.

Reference materials:

[1] New immunotherapy approach wiped out tumors in two patients with advanced lung cancer, study reports.
Retrieved August 16, 2021, from https:// -out-tumors-advanced-lung-cancer/

[2] Creelan et al.
, (2021).
Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial.
Nature Medicine, https://doi.
org/10.
1038/s41591-021 -01462-y

[3] Veatch et al.
, (2021).
Tumor-infiltrating lymphocytes make inroads in non–small-cell lung cancer.
Nature Medicine, https://doi.
org/10.
1038/s41591-021-01445-z

[4] Iovance Biotherapeutics Reports Second Quarter and First Half 2021 Financial Results and Corporate Updates.
Retrieved August 16, 2021, from https://ir.
iovance.
com/news-releases/news-release-details/iovance-biotherapeutics-reports -second-quarter-and-first-half

[5] Tumor Infiltrating Lymphocyte Cell Therapy for Treatment of Solid Tumors.
Retrieved August 16, 2021, from https://ir.
iovance.
com/static-files/76acd330-3c49-4678-9929-a14177f3a657

[6] Wang et al.
, (2021).
Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors.
BMC Medicine, https://doi.
org/10.
1186/s12916-021-02006-4