October 20, 2021

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What immunotherapy can treat solid tumors more effectively in future?

What immunotherapy can treat solid tumors more effectively in future?

What immunotherapy can treat solid tumors more effectively in future?

Solid tumors, which account for 90%, have become the main battlefield for anti-cancer, and major cellular immunotherapies have begun to exert their strength.

Immunotherapy has become a new hope for humans to fight cancer, and CAR-T therapy is one of the most promising tumor immunotherapy in recent years.

This technology has made great progress in the treatment of various malignant tumors and has been successfully applied to the treatment of various hematological malignancies.

According to data provided by Clinical Trials.gov, as of April 2021, there are a total of 1,358 active cell therapy trials; compared with the 24% growth from 2019 to 2020, there is an increase of 43% from 2020 to 2021.

Most of this increase is due to CAR-T cell clinical trials, which have increased by 83% since the 2019 update, and more trials have tested other cell therapies, TCR-T cell therapies and TIL cell therapies. However, the number of NK/NKT cells tested declined and has not yet fully recovered.

What immunotherapy can treat solid tumors more effectively in future?

However, it is worth mentioning that most of the above trials are still concentrated in the field of hematological tumors (non-solid tumors), and there are still difficulties in the broad field of solid tumors, and solid tumors are the “main battlefield” of anti-cancer. As pointed out in the latest global cancer data in 2021, about 90% of cancer incidences are caused by solid tumors, but there are few clinical trials of cell therapy for solid tumors (solid tumors account for 40%, and most of them are in early stages) . It can be seen that solid tumors are still a difficult point in cellular immunotherapy.

What immunotherapy can treat solid tumors more effectively in future?

Picture a is a cell therapy target for hematological tumors; b is a cell therapy target for solid tumors

Immunotherapy is essentially different from surgery, traditional chemotherapy and targeted therapy. It targets immune cells rather than cancer cells. This new type of therapy activates or transforms the human immune system’s anti-tumor immunity, making it a weapon to attack cancer cells. Also known as the “fourth therapy” for cancer.

Cellular immunotherapy is to collect the body’s own immune cells, then process them in vitro, culture and expand them to enhance their targeted killing function, and then return them to the body to activate and enhance the body’s immune function to achieve the purpose of anti-tumor and anti-virus.

In the face of solid tumors, which account for more than 90%, major cellular immunotherapies have made efforts to overcome difficulties and made many outstanding research progress. Today, the editor of Cancer Free Home will take stock of several cellular immunotherapies that have made major international research advances, hoping to provide a new treatment option for cancer friends who are helpless and don’t know which therapy to try.

CAR-T cell therapy

Speaking of the hottest cancer therapy in recent years, CAR-T in immunotherapy is definitely a widely publicized “anti-cancer star”. The Internet, TV, radio and other media are overwhelming, and the capital market is also rushing for it. Big institutions and major hospitals chase after me, as if CAR-T is the “nirvana” to overcome cancer. So, where is CAR-T sacred?

CAR-T therapy is chimeric antigen receptor T cell immunotherapy, a new type of precision targeted therapy for tumor treatment. Through genetic engineering technology, T cells are activated, and the positioning navigation device CAR (Tumor Chimeric Antigen Receptor) is installed to transform the ordinary “warrior” of T cells into “super fighters”, namely CAR-T cells, which specifically identify tumors in the body Cells, and effectively kill tumor cells, so as to achieve the purpose of treating malignant tumors.

However, the clinical efficacy of CAR-T treatment on solid tumors is not satisfactory. The main reason is that there are many difficulties in the cell therapy of solid tumors, such as the heterogeneity of different types of solid tumors, the lack of unique tumor-associated antigens as CAR-T targets, the inability of T cells to effectively home to the tumor site, Insufficient CAR-T cell persistence and the complex microenvironment within the tumor have a suppressive effect on immunity.

In view of the many difficulties, researchers should pay more attention on :

1. Promote the transport of T cells to the tumor site:

(1) Use chemokine receptors to modify CAR-T cells to improve the homing of CAR-T cells to the tumor site.

(2) Local administration of CAR-T cells to the tumor site.

2. Improve the immunosuppressive microenvironment:

In solid tumors, even if CAR-T cells can migrate to the tumor site, CAR-T cells face a hostile tumor microenvironment (TME).

3. Select the appropriate antigen according to the tumor microenvironment:

With the increasing number of clinical trials of CAR-T therapy for solid tumors, these trials are now summarized to explore the method of selecting suitable targets based on the specific tumor microenvironment. The following figure shows the classification of antigens for different cancers.

What immunotherapy can treat solid tumors more effectively in future?

Classification of CAR-T targets for different cancers

Gastric cancer and pancreatic cancer

At the annual meeting of the European Society of Medical Oncology (ESMO) held on September 16-21, the CT041, an autologous CAR-T candidate product targeting Claudin 18.2 (CLDN18.2) developed by Keji Pharmaceutical, demonstrated its role in digestive system tumors. The outstanding curative effect in, it can be said to be brilliant!

Claudin 18.2 (CLDN 18.2) is a gastric-specific membrane protein, which is considered a potential therapeutic target for gastric cancer and other cancer types. Based on this, Chinese researchers developed the first CAR-T cell targeting Claudin 18.2 in the world.

As of April 8, 2021, 37 patients with advanced gastrointestinal tumors with positive CLDN18.2 expression were included, including 28 cases of gastric cancer/gastroesophageal junction cancer, 5 cases of pancreatic cancer and 4 cases of other types of solid tumors. Approximately 84% of the patients had received at least 2 lines of treatment in the past, and the median number of metastatic organs was 3.

Exciting research data !

1. Total curative effect:

The objective remission rate of all patients reached 48.6%, and the disease control rate reached 73%; the total objective remission rate of all patients with gastric cancer was 57.1%.

2. Gastric cancer patients who have previously received at least 2 lines of treatment failure:

the objective remission rate was 61.1%, and the disease control rate was 83.3%.

3. 28 cases of gastric cancer/gastroesophageal junction cancer in each subgroup:

Among the patients with poor prognosis such as previous PD-(L)1 inhibitor treatment failure, peritoneal metastasis, signet ring cell carcinoma, etc., and no effective treatment, the objective response rate Can be maintained at 50% or above.

4. Safety:

CT041 is generally well tolerated, and there is no treatment-related death or immune cell therapy-related neurotoxic syndrome (ICANS).

In addition to CT041 is currently undergoing clinical trials, another target Claudin 18.2 for recurrent or metastatic advanced gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma) after total gastrectomy/subtotal gastrectomy. The CAR-T cell preparation named LCAR-C18S is also under clinical recruitment.

Liver cancer

At this year’s ASCO annual meeting, medical researchers announced for the first time the latest clinical research data of CAR-T drug (Ori-CAR-001) targeting GPC3 in the treatment of relapsed/refractory hepatocellular carcinoma. The preliminary data of the study showed that Ori-CAR-001 showed good safety and effectiveness in GPC3-positive relapsed/refractory patients.

As of March 10, 2021, a total of 11 relapsed subjects who received cell infusion were enrolled. All subjects suffered from advanced hepatocellular carcinoma, and were ineffective after chemotherapy, TACE (hepatic artery chemoembolization) and targeted therapy. Among the 9 evaluable subjects, 4 achieved partial remission (PR), 3 achieved stable disease (SD), and 2 developed disease progression (PD). The objective response rate was 44%, and the disease control rate reached 78%.

On July 29, the internationally renowned journal “Journal of Hematology & Oncology” published a clinical study of Chinese medical researchers successfully transforming CAR-T technology. The target of CAR-T product selection mentioned in the study was In glypican-3 (GPC3) and mesothelin (MSLN), the reported treatment results are particularly amazing!

One of the patients with advanced liver cancer received intratumoral injection of CAR-T. After treatment, the metabolism of liver lesions basically disappeared.

What immunotherapy can treat solid tumors more effectively in future?

After 60 days of injection, although the size of the two lung nodules did not change significantly, the liver tumor lesions shrank significantly on the 10th day and disappeared completely after the 32nd day of the injection

What’s more, a patient with advanced pancreatic cancer received CAR-T treatment with intravenous infusion. After treatment, the whole body’s lesions basically achieved complete disappearance of metabolic activity.

What immunotherapy can treat solid tumors more effectively in future?Complete remission was achieved after 240 days of treatment, no other enlarged lymph nodes were seen, and the patient’s lesions disappeared completely

Ovarian cancer

On February 18, the world-class academic journal “Journal of Cancer Immunotherapy” published the research results of Chinese medical researchers using CAR-T autocrine PD-1 antibody for the treatment of solid tumors. Clinical data showed that a patient with advanced refractory ovarian cancer who used this treatment had a progression-free survival of 5 months and a survival of 17 months.

The results indicate that the combination of CAR-T cells and apatinib will become a new treatment method for advanced/refractory ovarian cancer.

Non-small cell lung cancer

301 Hospital took the lead in developing CAR-T therapy in China, with remarkable results. Professor Han Weidong once reported the use of EGFR-targeted CAR-T to treat patients with advanced refractory non-small cell lung cancer with strong EGFR expression (EGFR expression exceeding 50%).

The results of the study showed that the efficacy of 11 patients can be evaluated: 2 patients have significantly reduced tumors, and 5 patients have stable disease.

In Figure A, patient 1 was infused with CAR-T cells. CT scan showed that his pleural effusion was reduced, and the metastatic hilar lymph nodes and pleural nodules were slightly reduced (arrows).

The CT image in Figure B shows that the primary tumor of patient 8 has shrunk (arrow);

The CT examination in Figure C found that patient 9’s pleural effusion absorption and lung lesions significantly subsided after CAR-T treatment.

Tumors of the biliary system

In March 2018, the team of Professor Han Weidong from the PLA General Hospital announced the preliminary results of using EGFR CAR-T technology to treat biliary system tumors.

The included patients were all patients with unresectable malignant tumors of the biliary system that were strongly positive for EGFR (>50% of cancer cells express EGFR). A total of 19 patients were included, including 14 cases of cholangiocarcinoma and 5 cases of gallbladder cancer.

The results of the study showed that 17 patients could be evaluated, of which the tumor of one patient with cholangiocarcinoma disappeared completely. So far, the curative effect has been maintained for 22 months, and no recurrence of the disease has been found. The disease of 10 patients was stable, the curative effect remained 2.5~15.5 months, and the median progression-free survival period was 4 months.

CT scan images of patient 1 before CART-RGFR cell therapy and 1, 3, 10, and 15 months.
The red arrow indicates the primary tumor and retroperitoneal lymph node metastasis.

In the study, 10 patients experienced grade 3 to 4 side effects during chemotherapy preconditioning, and they all returned to normal after active treatment.

Tumor infiltrating lymphocyte (TIL) treatment

TILs therapy, to put it simply, is to separate and purify the lymphocytes in the surgically resected tumor tissue, select the lymphocytes that can specifically anti-cancer, and reinfuse after amplification and activation. This type of therapy has a history of more than 30 years and was first used for malignant melanoma. In recent years, it has given good data in various solid tumors such as cervical cancer and lung cancer.

This therapy is equivalent to pulling back veterans with combat experience directly from the battlefield. After a round of “political review” and a “competition” of professional capabilities, the traitors and traitors are eliminated as much as possible, leaving the strongest combatants, providing supplies, and then Return to the battlefield to continue fighting.

The disease control rate is 89%! LN-145 therapy won the FDA breakthrough therapy title!

In June 2019, the FDA approved the tumor-infiltrating lymphocyte (TIL) treatment method LN-145 as a breakthrough treatment designation. This is the first time that a cellular immunotherapy for solid tumors has won this award. I believe it is only a matter of time before the launch. 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 grant is based on the data from the ongoing active second phase of innovaTIL-04 (C-145-04). The summary data shows that the overall response rate (ORR) for TIL treatment in patients with advanced cervical cancer is 44%. The control rate is 89%!

Typical patient cases

Next, the editor specifically finds some relevant clinical cases about TILs in the treatment of various types of cancer, for your reference, and hope to bring you more hope of survival!

No recurrence in 9 years, TILs therapy is very effective in treating melanoma!

A phase I/II feasibility study for the treatment of metastatic melanoma with TIL to evaluate the feasibility and clinical effectiveness.

A total of 10 patients received treatment, and 5 showed obvious clinical response, including 2 patients in complete remission, and continued treatment for more than 7 years. One patient had stable disease for more than 2 months, and the remaining 4 showed progressive disease.

Patient 3 with the best treatment effect was a 46-year-old male with BRAF V600E mutation-positive melanoma, accompanied by lymph node metastasis, liver metastasis and enlarged left adrenal gland.

After TIL treatment, the patient remained disease-free for more than 9 years. The waterfall chart below shows the best response of 10 patients. Among them, the picture of patient 3’s leg tumor gives the strongest proof of the efficacy of neoantigen TILs.

Breast cancer: 81 billion T cells were transfused back into the patient’s body, and her tumor completely resolved after 10 days

In 2015, 49-year-old Judy Perkins was an ER+/HER- advanced breast cancer patient who had received standard treatments such as chemotherapy and endocrine, but all were resistant and had multiple metastases throughout the body.

In view of the seriousness of the disease, there is no way to treat it by conventional methods, so the doctor predicts that she can only live for at most 3 months. Earlier, she had also received clinical trials of immunotherapy.

The researchers found tumor-infiltrating immune cells in her tumor. After isolating these immune cells, the scientists decided to expand them in large quantities and then infuse them back into the patient’s body.

A week later, Judy Perkins felt a noticeable change in his body. For example, the tumor on her chest felt gradually shrinking. After another week or two, the tumor in the chest cavity disappeared. Currently, she has been cancer-free for 6 years!

The yellow arrow on the left is the location of the tumor before treatment; the right is the re-examination 14 months after the end of treatment: the tumor has completely disappeared

Cholangiocarcinoma: The first super survivor to receive TILs therapy has lived for 12 years!

The autumn of 2009 was unforgettable for 41-year-old Melinda Bachini. On the day of her son’s 14th birthday, she was diagnosed with a rare bile duct cancer and sentenced to life with only a few months left. She struggled and was unwilling to be reconciled. Fortunately, her fate is not thin to her, and she has now become a survivor of advanced cholangiocarcinoma who has survived for 12 years!

From only a few months of survival to becoming a super survivor, the new immunotherapy that gave Melinda a new life is tumor infiltrating lymphocyte (TIL) therapy.

What played a huge role in Melinda was the second input of 127 billion immune cells. At first, her tumor size was reduced by 60%. After the trial was over, she was treated with the immune checkpoint inhibitor pembrolizumab, which successfully shrank the tumor. At present, any part of the body has been guaranteed to be in a cancer-free state.

TILs therapy has shown excellent therapeutic effects in a variety of solid tumors, but not all patients are suitable for this therapy. First of all, patients with solid tumors must be able to get the tumor tissue; secondly, they must be able to successfully separate from the tumor tissue. Lymphocytes; In addition, the isolated lymphocytes have sufficient activity and can be fully expanded and cultured. Any problem in any link cannot support the patient to complete the treatment. Therefore, whether the treatment can benefit from the treatment needs to be assessed according to the specific situation of the patient. Therefore, it is necessary to communicate with experts before treatment.

At present, TILs therapy is more effective in the treatment of metastatic lesions, and is especially suitable for the removal of metastatic lesions after surgery and prevention of tumor recurrence. For large solid tumors, TILs therapy has limited therapeutic effects and requires other methods to co-treat.

TCR-T therapy

Both CAR-T cells and TCR-T cells are T cells modified by genetic engineering technology. Compared with CAR-T therapy, TCR-T therapy has unique advantages in the field of solid tumor treatment.

TCR-T cell therapy can recognize tumor-specific antigens derived from the surface of cell membranes or intracellularly. It has been applied in clinical applications from the very beginning of basic immune research. It has shown initial efficacy in solid tumors and has become the most likely field in solid tumors. A breakthrough in T cell immunotherapy!

What is TCR-T cell therapy?

The main mechanism of TCR-T technology is to introduce new genes into ordinary T cells, so that the modified T cells can express TCR (T cell receptor) that can effectively recognize tumor cells, thereby guiding T cells to kill tumors cell.

New dawn for advanced liver cancer! TCR-T therapy gives cancer patients complete remission

As early as at the International Liver Disease Conference (ILC) in 2020, a new TCR-T therapy for liver cancer, ADP-A2AFP, based on T cells, caused quite a stir and made new breakthroughs in new therapies for liver cancer.

Among the included patients, one patient showed complete remission (CR) of cancer cell progression, and the alpha-fetoprotein (AFP) of the remaining participants also showed varying degrees of decline, which means that the trial has made progress. It also shows that the therapy is effective for the treatment of advanced liver cancer.

The 9 patients involved have all received surgery and conventional radiotherapy and chemotherapy, but they have failed or intolerated. Among the 4 patients who received the highest dose of treatment, 1 patient achieved complete remission. CT scans showed that all the lesions in the patient’s body had disappeared, and the complete remission had lasted for more than half a year without any recurrence!

The best response of other patients (cohort 1, cohort 2) is stable disease. One patient in cohort 2 did not reduce the volume of the primary lesion after 1 month of treatment, but the volume of the mediastinal lymph node metastasis was significantly reduced!

Therefore, TCR-T therapy targeting AFP (alpha-fetoprotein) can kill tumor cells expressing AFP. Based on the positive results of this study, researchers are expected to expand the maximum dose to 5 billion cell therapy. We look forward to this The updated data of the research is made public!

The disease control rate is 86%! The latest data of the new TCR-T therapy is released!

In the phase 1 trial code-named SURPASS, a total of 25 patients with advanced metastatic cancer were recruited, and these patients received an average of 3 treatment options, which can be said to be clinically difficult to treat. As of August 2, 2021, these patients have received ADP-A2M4CD8 cell therapy, and finally 22 patients can be evaluated.

Experimental results:

The data is very exciting. The first phase of the trial shows that the efficacy and durability of this emerging therapy are very promising, and there is a response to 5 types of solid tumors.

1. The overall objective response rate (ORR) is 36%, and the disease control rate (DCR) is as high as 86%;

2. A patient with ovarian cancer reported complete remission and continued remission 6 months after the infusion;

3. As of the data cutoff, 11 patients are still undergoing research. Of the 8 responders, 5 were still responding, and the remaining patients had been progression-free for more than 24 weeks.

In addition, there is a TCR-T technology afamitresgene autoleucel (afami-cel, formerly known as ADP-A2M4) for the MAGE-A4 cancer antigen, which is used in a variety of solid tumor types, including synovial sarcoma, head tumor, and cervical cancer Remission has been achieved in both lung cancer and lung cancer, and many patients have experienced long-lasting responses, which means that this new type of TCR-based emerging technology is a new hope for breaking solid tumors in the future.

Links to related articles: TCR-T therapy is emerging! The “leader” who is challenging the refractory solid tumors has started on the middle and advanced stages of liver cancer!

All in all, compared with CAR-T, TCR-T has the advantage of higher safety, and the disadvantage is that TCR-T needs to be matched first like bone marrow transplantation; then, the expression of specific proteins in the patient’s tumor tissue must be detected. Only the patients with high expression of the corresponding specific protein and the matching type can be used, otherwise there will be no effect.

In addition to the above-mentioned cellular immunotherapy, there is also CTL therapy (using proteins unique to cancer cells that are absent or low in normal cells as bait to pick out the “one in a million” lymphocytes in the peripheral blood that can truly fight cancer. It is selected, and then further improved and expanded in vitro, and then returned to the patient), dendritic cell vaccine (a group of heterogeneous immune cells with the strongest antigen presentation function, and the only professional antigen that can activate naive T cells) Presenting cells, therefore also known as the “sentinel” of the immune system), other cancer vaccines, etc. are also constantly improving technology, striving to overcome solid tumors as soon as possible.

The future can be expected! Cellular immunotherapy is the ultimate weapon to overcome cancer!

According to the latest statistics, compared to patients with advanced lung cancer, gastric cancer, liver cancer and other patients who only receive surgery, radiotherapy, and chemotherapy, adjuvant cell immunotherapy can extend the survival time of patients and significantly improve the effectiveness of the data. The reason lies in the advantages of cellular immunotherapy:

  1. After surgery or patients who missed the opportunity of surgery, chemotherapy and radiotherapy are needed, but chemotherapy or radiotherapy cannot achieve the expected results. Only supplemented by cellular immunotherapy can achieve good results.
  2. Cellular immunotherapy has a synergistic anti-tumor effect in the intermittent period of chemotherapy and radiotherapy, making patients more sensitive to the side effects of chemotherapy and radiotherapy, enhancing the anti-cancer effect, and improving the comprehensive treatment effect of tumors.
  3. Cellular immunotherapy is a potential alternative therapy for malignant melanoma, kidney cancer and other special types of malignant tumors that are sensitive to chemotherapy and radiotherapy.
  4. Combining cellular immunotherapy can significantly improve the immune system function of tumor patients, help to remove residual cancer cells and micrometastasis after surgery, and significantly reduce the incidence of local recurrence and distant metastasis.
  5. After in vitro amplification, immune cells can directly kill tumor cells or stimulate the body’s tumor immune response, so as to achieve the purpose of controlling tumor recurrence and metastasis, thereby prolonging the survival period of patients and improving the quality of life.
  6. Compared with traditional therapies, cellular immunotherapy is more targeted, using the body’s own immune cells to kill tumors, which is safer and has fewer side effects.

(source:internet, reference only)

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