Speaking of cellular immunotherapy, you may be familiar with the famous chimeric antigen receptor T-cell (CAR-T) therapy, which claims 1.2 million shots per injection. In fact, the tumor tissue removed by surgery of tumor patients contains a group of immune cells with the strongest cancer-killing ability - tumor-infiltrating lymphocytes .
TILs therapy can be said to be an "ancient" cell therapy with a history of more than 30 years. As early as 1988, Director Steven Rosenberg, an American cancer researcher, invented this cancer treatment method through the research and improvement of TIL cells.
Like CAR-T therapy, TILs therapy also belongs to the category of adoptive cell therapy. The difference is that CAR-T therapy has had a significant effect on hematological malignancies caused by B cells, but most solid tumors cannot respond significantly to chimeric antigen receptor T cells. TILs are specific immune cells (T cells) that naturally exist in tumors. They have a natural killing ability against solid tumors. They were first used in malignant melanoma. In recent years, they have given good data in various solid tumors such as cervical cancer and lung cancer.
China’s first TIL cell drug GT101 was approved by the China Food and Drug Administration
April 22, 2022, According to the official website of the Center for Drug Evaluation of the China National Medical Products Administration (CDE), GT101 injection (acceptance number: CXSL2200061) independently developed by Shali Biotech has officially obtained the implicit clinical trial license from the National Medical Products Administration (NMPA). It is worth mentioning that GT101 is the first clinically approved tumor-infiltrating lymphocyte drug (TIL) in China, which is a milestone!
It is reported that GT101 injection has demonstrated good drug safety, obvious tumor killing and clinical effectiveness in clinical trials (IIT) initiated by early researchers, and is expected to become a new choice for patients with solid tumors such as melanoma, cervical cancer, non-small cell lung cancer, and in China.
Screenshots from the official website of "NEJM" 
The median follow-up was 33 months, and the results showed:
. Overall effective rate (RR): TIL group was 48.8%; Y drug group was 21.4%;
. The complete response rate was 20.2% in the TIL group; 7.1% in the Y drug group;
. The median progression-free survival time was 7.2 months in the TIL group; 3.1 months in the Y drug group;
4. The median overall survival : TIL group was 25.8 months; ; Y drug group was 18.9 months;
5. Safety: is basically similar. It is worth mentioning that the health-related quality of life scores of patients in the TIL group were higher than those in the Y drug group.
This multi-center phase 3 study is the first randomized trial of TIL therapy in solid tumors. The results of the study show that compared with Y drug, TIL significantly improved the median progression-free survival time in the treatment of advanced melanoma. The vast majority are patients refractory to anti-PD-1 monoclonal antibodies. TIL may be a new treatment option for these patients.
Looking at the entire industry, Lovance, as the current leader in the field of TILs cell therapy, has earlier submitted a rolling marketing application for the innovative therapy LN-144 (Lifileucel) to the FDA for the treatment of advanced melanoma that has progressed after PD-1/PD-L1 treatment.
According to the latest news from Iovance, the completion time of the Biological Products License Application (BLA) for TIL therapy lifileucel is expected to be extended to the first quarter of 2023. If successfully approved, lifileucel will become the first TILs therapy.
Cervical cancer
The disease control rate is 89%! LN-145 therapy received FDA breakthrough therapy designation!
In June 2019, the FDA approved the tumor-infiltrating lymphocyte (TIL) treatment method LN-145 as a breakthrough therapy designation. This is the first time that a cellular immunotherapy for solid tumors has received this award. I believe it is only a matter of time before it is launched. Once approved by the FDA, this will be the first cellular immunotherapy for solid tumors and will bring huge survival benefits to cancer patients.
The FDA's award is based on data from the ongoing active Phase 2 trial of innovaTIL-04 (C-145-04), with summary data showing an overall response rate (ORR) of 44% for TIL therapy in patients with advanced cervical cancer.
There were 27 evaluable patients at the data cutoff of February 4, 2019.
results showed:
1. 44% (12) patients had an effect, including 1 complete response, 9 partial responses and 2 unconfirmed partial responses;
2. The disease control rate was 89%;
3. The median follow-up time was 3.5 months, and 11 of 12 patients had sustained response;
4. No serious side effects occurred.
5. The disease control rate is 89%! The first cellular immunotherapy to combat solid tumors received the FDA breakthrough therapy designation!
75% of patients achieved complete remission! Domestic scholars test their skills!
On August 1, 2022, Chinese medical researchers also used TIL cell therapy to assist immunotherapy in patients with locally advanced cervical cancer. The study included 27 patients who received concurrent chemoradiotherapy and obtained tumor tissue through minimally invasive surgery. Sufficient TIL cells could be obtained in 20 patients, with a success rate of 74.1%.
Until the last follow-up on March 1, 2022, 12 patients successfully received TIL cell reinfusion, 9 patients achieved complete tumor remission (one or more tumors completely regressed) after concurrent chemoradiotherapy and TIL cell reinfusion. The complete response rate was 75%; the duration of disease control was 9 to 22 months; The longest therapeutic effect has been maintained for more than 2 years.
In this clinical trial, there were two successful cases of complete remission of tumors (Patient No. 19 and Patient No. 11). The specific efficacy of is as shown in the figure:
Breast cancer
In 2018, the internationally renowned journal "Nature Medicine" published a case of breast cancer patients successfully treated with TILs therapy. A case of a 49-year-old woman with estrogen receptor (ER)-positive and ERB-B2 receptor tyrosine kinase 2 (HER2) Negative metastatic breast cancer, refractory to multiple lines of chemotherapy, was treated with TILs of 4 mutated proteins (SLC3A2, KIAA0368, CADPS2 and CTSB);
showed a 51% reduction in target tumor burden 6 weeks after cell transfer; 22 months after cell transfer (last assessment), the patient's tumor was completely gone and no progression or recurrence occurred 4 years later.
Breast cancer: 81 billion T cells were infused back into the patient's body, and her tumor completely regressed 10 days later.
In 2015, 49-year-old Judy Perkins was a patient with ER+/HER- advanced breast cancer. She had received standard treatments such as chemotherapy and endocrine , but all were drug-resistant and had metastases throughout her body.
Due to the seriousness of the condition, there is no way to treat her through conventional methods, so doctors predict that she can only live for 3 months at most. She had also undergone clinical trials of immunotherapy before.
The researchers found tumor-infiltrating immune cells in her tumor. After isolating these immune cells, the scientists decided to expand them in large numbers and infuse them back into the patient.
After a week, Judy Perkins felt that her body had changed significantly. For example, the tumor she had on her chest felt like it was gradually shrinking. After another week or two, the tumor in the chest was gone.Currently, she has been cancer-free for 6 years!
non-small cell lung cancer
powerful combination! TILs therapy combined with PD-1 can still achieve complete remission in patients with advanced metastatic lung cancer
In fact, as early as August 12, 2021, a study by researchers from the Lung Cancer Center of Excellence at Moffitt Cancer Center was published in the internationally renowned medical journal "Nature". The clinical efficacy of TILs therapy combined with PD-1 in patients with advanced metastatic lung cancer after resistance to PD-1 has been reported!
TILs therapy strengthens the immune system by providing more T cells to mount an attack, while checkpoint inhibitors prevent tumors from inactivating T cells that infiltrate the tumor.
0 patients with advanced non-small cell lung cancer were initially included in the study, including 215 cases of lung adenocarcinoma and 25 cases of lung squamous cell carcinoma. Each patient had one or more tumors removed. The tumors are sent to a laboratory, where each one is dissected and the infiltrating immune cells removed. These cells, called tumor-infiltrating lymphocytes, are cultured and expanded before being injected into the patient. After patient
underwent biopsy to extract tumor tissue, received 4 courses of Nivolumab, 240 mg once every two weeks. If patients experience disease progression after checkpoint inhibition therapy, they will receive personalized TILs followed by nivolumab maintenance therapy.
Researchers successfully expanded TIL infusions in 95% of patients, with 16 of 20 patients receiving TIL infusions because their disease progressed after initial nivolumab treatment. The combination treatment produced promising antitumor activity, with 11 of 116 patients experiencing tumor regression. Two patients had complete tumor remission after 18 months (one and a half years), and two patients had partial remission or maintained clinical remission.
Colorectal cancer
7 malignant tumors were completely wiped out by 148 billion immune cells
In September 2013, Celine Ryan was diagnosed with advanced colorectal cancer. She used many treatments, but unexpectedly, the cancer that was once limited to the colon was spreading to the lungs, growing 7 tumors, and the prognosis was extremely poor.
Fortunately, she got the immunotherapy plan proposed by her doctor, understood that her cancer was caused by a defect in the KRAS gene, and participated in a TILs clinical trial from the National Cancer Institute.
The researchers selected a group of tumor-infiltrating lymphocytes with high immune activity from her body for culture. Finally, the researchers injected 148 billion tumor-infiltrating lymphocytes cultured in vitro into Celine's body, allowing these tumor-infiltrating lymphocytes to fight cancer cells.
Over the next nine months, six of the seven tumors in Celine's lungs shrank significantly and eventually disappeared. The last tumor that didn't respond to treatment was surgically removed. Today, no cancer cells can be detected in her body and she has lived cancer-free for five years.
Head and neck cancer
TILs join forces with PD-1! Overcome difficult-to-treat tumors such as head and neck squamous cell carcinoma!
From November 10th to 14th, 2021, at the Annual Conference on Immunotherapy of Cancer (SITC), Iovance announced the clinical data of TILs therapy combined with pembrolizumab in the treatment of advanced cancer patients and the treatment of relapsed and refractory lung cancer, which shocked the audience!
Latest clinical data show that powerful TIL therapy has outstanding potential in a variety of solid tumor cancers and various treatment dilemmas. Combining TIL with pembrolizumab as first-line treatment for clinically refractory tumors such as advanced cervical cancer, melanoma, and head and neck cancer may improve response rates.
In the 2A cohort of the IOV-COM-202 trial, 18 patients with advanced head and neck squamous cell carcinoma experienced an objective response after receiving the combination of Lifileucel + Pembrolizumab. The ORR was 38.9% (7/18), including 1 case of complete response, 1 case of unconfirmed complete response, 4 cases of partial response, 1 case of unconfirmed partial response, and 7 cases of stable disease.50.0% (3/6) had ongoing confirmed response at a median of 7.8 months of study follow-up.
Cholangiocarcinoma
The first super-survivor cholangiocarcinoma patient to receive TILs therapy has lived for 13 years now!
The autumn of 2009 was an unforgettable experience for 41-year-old Melinda Bachini. On her son's 14th birthday, she was diagnosed with a rare form of bile duct cancer and was sentenced to only a few months to live. She struggled with pain but was unwilling to give in. Fortunately, fate has been kind to her, and is now a 13-year survivor of advanced cholangiocarcinoma!
From having only a few months left to survive to becoming a super survivor, the new immunotherapy that gave Melinda a new life was tumor-infiltrating lymphocyte (TIL) therapy .
What played a huge role in Melinda was the second infusion of 127 billion immune cells. Initially, her tumor volume shrank by 60%. After the trial, she received treatment with the immune checkpoint inhibitor pembrolizumab, which successfully shrank the tumor. Currently, any part of her body is guaranteed to be cancer-free.
Ovarian cancer
In addition, in terms of ovarian cancer (OC), researchers are trying to combine checkpoint inhibitors (ICIs) with TILs for treatment.
Patients with advanced metastatic high-grade serous OC undergoing surgery after receiving ipilimumab received TIL therapy followed by low-dose IL-2 and nivolumab. The results showed that one patient achieved partial response, and the other five patients experienced stable disease for up to 12 months. It has been initially confirmed that the combination of immune checkpoint inhibitors and TILs therapy is feasible and safe.
Osteosarcoma
A total of 60 patients with refractory osteosarcoma were included in the study and divided into 2 groups. Thirty of the patients received nivolumab (nivolizumab, K drug) monotherapy, while the other 30 patients received TILs therapy plus nivolumab.
The results showed:
As of June 1, 2020, the objective response rate (ORR) of group 2 reached 33.3%, and 2 of the 10 patients had imaging examination showing that the lesions had completely disappeared.
Mean progression-free survival (mPFS): 3.8 months vs 5.4 months;
Mean overall survival (mOS): 6.6 months vs 5.2 months, Compared with the group using K drug alone, the overall survival of the combination therapy doubled!
Tailor-made, TILs therapy accurately kills tumor cells
TILs therapy is equivalent to directly pulling veterans with combat experience from the battlefield. After a round of "political review" and "competition" of professional capabilities, we try to eliminate the traitors and traitors, leaving the ones with the strongest combat effectiveness, providing supplies, and then returning them to the battlefield to continue fighting.
In addition to non-small cell lung cancer , TILs therapy also shows great potential in melanoma, cervical cancer, cholangiocarcinoma, colorectal cancer, breast cancer, head and neck, sarcoma, gallbladder cancer and other malignant tumors. Please check the related links at the end of the article. Various studies that have been developed show that TILs treatment will continue to be improved and developed, and will eventually become a new weapon for humans to fight cancer. Although this new type of immunotherapy is not yet on the market, a number of clinical trials targeting various solid tumors (non-small cell lung cancer, colorectal cancer, ovarian cancer, melanoma...) have been conducted around the world.
In fact, TILs therapy is particularly unique. It is very different from general cellular immunotherapy and is considered to be "tailor-made" for patients.
1 Immune cells come from different sources:
TIL immune cells come from tumor tissue, while most other cellular immunotherapies come from blood. This directly determines the ability of immune cells to recognize tumors. It is estimated that more than 60% of immune cells isolated from tumors can recognize tumors, while less than 0.5% of immune cells isolated from blood.
2 Using mutations to accurately identify cancer cells
This new type of therapy is not a simple amplification and infusion, but to determine the specific mutations in the patient's case, and then use the mutation information to find the T cells that can most effectively target these mutations, and finally extract the T cells that specifically have the mutation in the cells in the patient's tumor. These cells have the ability to accurately identify cancer cells. 3 The effect is better when combined with PD-1 inhibitors These immune cells are cultured in vitro and reinjected into the patient. At the same time, the research team used a combination of the immune-enhancing drug interleukin 2 and another "star anti-cancer drug" PD-1 inhibitor Keytruda. Keytruda is another type of immunotherapy immune checkpoint blockade, which has significant effects in some cancers. In addition to the above-mentioned tumor-infiltrating lymphocyte therapy , there are also: Extended reading
. CAR-T therapy: CAR-T therapy (chimeric antigen receptor T cell immunotherapy) is a new type of precise targeted therapy for the treatment of tumors, but the mechanism is more complex than PD-1. Through genetic engineering technology, T cells are activated and equipped with a positioning navigation device CAR (tumor chimeric antigen receptor), transforming ordinary "soldiers" of T cells into "super soldiers", namely CAR-T cells, which specifically identify tumor cells in the body and efficiently kill tumor cells, thereby achieving the purpose of treating malignant tumors.
. Dendritic cell vaccine: is a heterogeneous group of immune cells with the strongest antigen-presenting function. It is the only professional antigen-presenting cell that can activate initial T cells, so it is also called the "sentinel" of the immune system.
. TCR-T therapy: Compared with CAR-T therapy, TCR-T therapy has unique advantages in the field of solid tumor treatment;
4. CAR-NK therapy: In 2020, CAR-NK immune cell therapy was included in the authoritative academic journal " Nature-Medicine " as one of the ten generations of notable developments in the biomedical field. It has outstanding advantages in solid tumors!
5. CTL therapy: uses the protein , which is unique to cancer cells and is absent or in very low content on normal cells, as bait to select the "one in a million" lymphocytes that can truly fight cancer in the peripheral blood, and then further improve and expand them in vitro, and then infuse them back to the patient.
This article is original from Cancer Free Home
