Review what immunotherapy can treat solid tumors more effectively in the future?

Immunotherapy has become a new hope for humans to fight cancer.

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.

The main reason for this increase is CAR-T cell clinical trials.

However, it is worth mentioning that most of the above-mentioned experiments 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

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

Immunotherapy is fundamentally different from surgery, traditional chemotherapy and targeted therapy

Cellular immunotherapy is to collect the body's own immune cells, process, culture and expand them in vitro to enhance their targeted killing function, and then return 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%, all major cellular immunotherapies have worked hard to overcome difficulties and have made many outstanding research progress

CAR-T cell therapy

Speaking of the most popular cancer treatment in recent years, CAR-T is undoubtedly the widely publicized "anti-cancer star" in immunotherapy

CAR-T therapy is a chimeric antigen receptor T cell immunotherapy, which is a new type of precise targeted therapy for tumors

However, the clinical efficacy of CAR-T in the treatment of solid tumors is not satisfactory

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

1.

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

 

2.

 

3.

 

 

Classification of CAR-T targets for different cancers

 

 

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Gastric cancer and pancreatic cancer

At the European Society of Medical Oncology (ESMO) annual meeting held from September 16 to 21, the autologous CAR-T candidate CT041 developed by Keji Pharmaceuticals targeting Claudin 18.

Claudin 18.
2 (CLDN 18.
2) is a gastric-specific membrane protein, which is considered a potential therapeutic target for gastric cancer and other types of cancer
.
On this basis, Chinese researchers have developed the world's first CAR-T cell targeting Claudin 18.
2
.

As of April 8, 2021, 37 patients with advanced gastrointestinal tumors with positive expression of CLDN18.
2 were enrolled, 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 patients have received at least two treatments in the past, and the median number of metastatic organs is 3
.

Exciting research data!

1.
Total efficacy:

The objective response rate of all patients reached 48.
6%, and the disease control rate reached 73%; the overall objective response rate of all patients with gastric cancer was 57.
1%
.

2.
Gastric cancer patients who have received at least 2 treatments in the past:

The objective response rate was 61.
1%, and the disease control rate was 83.
3%
.

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

For patients with poor prognosis such as PD-(L)1 inhibitor treatment failure, peritoneal metastasis, signet ring cell carcinoma and other patients without effective treatment, the objective effective rate can be maintained above 50%
.

4.
Security:

CT041 was well tolerated, with no treatment-related death or immune cell therapy-related neurotoxic syndrome (ICANS)
.

In addition to CT041 currently undergoing clinical trials, another targeting Claudin 18.
2 is used for advanced gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma) that recurred or metastasized after total gastric/subtotal gastrectomy
.
A 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 liver cancer
.
Preliminary research data show that Ori-CAR-001 has 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 patients were advanced liver cancer, which was ineffective after chemotherapy, hepatic artery chemoembolization, and targeted therapy
.
Of the 9 evaluable patients, 4 had partial remission (PR), 3 had stable disease (SD), and 2 had disease progression (PD)
.
The objective effective rate was 44%, and the disease control rate was 78%
.

On July 29, the internationally renowned journal "Journal of Hematology and Oncology" published a clinical research report on the successful transformation of CAR-T technology by Chinese medical researchers
.
The selected targets of CAR-T products mentioned in this study are In glypican-3 (GPC3) and mesthelin (MSLN).
The reported treatment results are particularly surprising!

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

After 60 days of injection, although there was no significant change in the size of the lung nodules, the liver tumor lesions were significantly reduced on the 10th day of the injection and disappeared completely on the 32nd day of the injection
.

More importantly, a patient with advanced pancreatic cancer received intravenous injection of CAR-T
.
After treatment, the systemic disease basically reached the complete disappearance of metabolic activity
.

Complete relief after 240 days of treatment, no other enlarged lymph nodes were seen, and the 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 to treat solid tumors
.
Clinical data showed that the progression-free survival period of one patient with advanced refractory ovarian cancer using this therapy was 5 months and 17 months, respectively
.

The results show that CAR-T cells combined with apatinib will become a new treatment method for advanced/refractory ovarian cancer
.

Non-small cell lung cancer

The 301 General Hospital of the People's Liberation Army took the lead in carrying out CAR-T treatment in China, and the effect was remarkable
.
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 exceeds 50%)
.

The results of the study showed that the curative effect of 11 patients can be evaluated: 2 patients have significantly reduced tumors, and 5 patients are in stable condition
.

In Figure A, patient 1 has been injected with CAR-T cells
.
CT showed a decrease in pleural effusion, and a slight decrease in metastatic hilar lymph nodes and pleural nodules (arrow)
.

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

Figure C CT examination revealed that patient 9 had pleural effusion absorption and lung lesions significantly resolved 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 biliary malignancies that were strongly positive for EGFR and were unresectable (>50% of cancer cells express EGFR)
.
A total of 19 patients, including 14 cases of cholangiocarcinoma and 5 cases of gallbladder cancer
.

The results of the study showed that 17 patients could be evaluated, and one patient with cholangiocarcinoma completely disappeared
.
So far, the curative effect has been maintained for 22 months, and no recurrence has been seen
.
The condition of 10 patients was stable, the curative effect was maintained for 2.
5 to 15.
5 months, and the median progression-free survival period was 4 months
.

CT scan images of patient 1 before EGFR CAR-T cell treatment and 1, 3, 10, and 15 months
.

The red arrow indicates the primary tumor and retroperitoneal lymph node metastasis
.

In this study, 10 patients experienced grade 3-4 side effects during chemotherapy pre-adaptation, and all returned to normal after active treatment
.

Tumor infiltrating lymphocyte (TIL) treatment

To put it simply, TILs treatment is to separate and purify the lymphocytes in the surgically resected tumor tissue, select lymphocytes with specific anti-cancer effects, expand and activate and then reperfusion
.
This therapy has a history of more than 30 years and was first used for malignant melanoma
.
In recent years, it has good data in various solid tumors such as cervical cancer and lung cancer
.

This therapy is equivalent to pulling veterans with combat experience directly from the battlefield
.
After a round of "political censorship" and "competition" of professional capabilities, the traitors were eliminated as much as possible, leaving the strongest combatants, providing supplies, and then returning 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 therapy designation
.
This is the first time that the cellular immunotherapy of solid tumors has won the award
.
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 approval is based on innovaTIL-04 (C-145-04)'s ongoing active Phase 2 data
.
Aggregated data shows that the overall effective rate (ORR) of TIL treatment for patients with advanced cervical cancer is 44%
.
The control rate is 89%!

Typical patient

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

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

Phase I/II feasibility study of TIL in the treatment of metastatic melanoma to evaluate its feasibility and clinical efficacy
.

A total of 10 patients received treatment, and 5 cases showed obvious clinical remission, of which 2 cases had complete remission and continued treatment for more than 7 years
.
1 case was stable for more than 2 months, and the other 4 cases progressed
.

The 3 patients with the best therapeutic effect were men, 46 years old, BRAF V600E mutation-positive melanoma, accompanied by lymph node metastasis, liver metastasis, and left adrenal gland enlargement
.

After TIL treatment, the patient remained disease-free for more than 9 years
.
The figure below shows the best response of 10 patients
.
Among them, the picture of patient 3's leg tumor most strongly proved the efficacy of neoantigen TILs
.

Breast cancer: 81 billion T cells were infused back into the patient, and the tumor completely resolved after 10 days

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

In view of the seriousness of the condition, there is no way to treat it with conventional methods, so the doctor predicts that she can only live up to 3 months
.
Earlier, she also underwent clinical trials of immunotherapy
.

Researchers found tumor-infiltrating immune cells in her tumor
.
After isolating these immune cells, the scientists decided to expand them in large numbers and then inject them into patients
.

A week later, Perkins felt a noticeable change in her body
.
For example, the tumor on her chest gradually shrank
.
After a 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 position of the tumor before treatment; the picture on the right is the re-examination after 14 months of treatment: the tumor has completely disappeared

Cholangiocarcinoma: The first super survivor to be treated with TILs has been alive for 12 years!

The autumn of 2009 was unforgettable for 41-year-old Melinda Bachini
.
On her son's 14th birthday, she was diagnosed with a rare type of bile duct cancer and sentenced to "death sentence", with only a few months left in her life
.
She struggled, unwilling to reconcile
.
Fortunately, her fate is not fragile.
She has now become a survivor of advanced cholangiocarcinoma and has survived for 12 years!

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

What played an important role in Melinda was the second infusion of 127 billion immune cells
.
At first, her tumor shrank by 60%
.
After the trial, she received treatment 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 good therapeutic effects in various solid tumors, but not all patients are suitable for this therapy
.
First, patients with solid tumors must be able to obtain tumor tissue; secondly, they must be able to be successfully separated from tumor tissue
.
In addition, the isolated lymphocytes have sufficient activity to be fully expanded and cultured
.
Any problems in any link cannot support the patient to complete the treatment
.
Therefore, whether the treatment can benefit from the treatment needs to be evaluated 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 metastases, and is especially suitable for the resection of postoperative metastases and the prevention of tumor recurrence
.
For large solid tumors, the therapeutic effect of TILs is limited, and other methods are needed for co-treatment
.

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 from the cell membrane surface or within the cell
.
It has been used clinically since the beginning of basic immunological research
.
It has shown preliminary efficacy in solid tumors and has become the most likely field in solid tumors
.

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 effectively recognizes tumor cells, thereby guiding T cells to kill tumor cells
.

The new dawn of advanced liver cancer, TCR-T treatment makes cancer patients complete remission

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

One patient had complete remission of tumor cell progression (CR), and the other patients had decreased alpha-fetoprotein (AFP) to varying degrees, indicating that the trial had progressed
.
This also shows that the therapy is effective for the treatment of advanced liver cancer
.

All 9 patients had received surgery, conventional radiotherapy, and chemotherapy, but all failed or were intolerable
.
Of the 4 patients who received the highest dose of treatment, 1 patient had a complete remission
.
CT scan showed that all the lesions in the patient's body disappeared, and the complete remission has lasted for more than half a year without 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 mediastinal lymph node metastasis was significantly reduced!

Therefore, TCR-T treatment for AFP (alpha-fetoprotein) can kill tumor cells that express AFP
.
It is estimated that based on the results of this study, the maximum dose will be expanded to 5 billion won
.
We look forward to the release of the latest data of this research!

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

In the phase I trial code-named "Beyond", a total of 25 patients with advanced metastatic cancer were recruited.
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 showed that the efficacy and durability of this emerging therapy is very promising, and it responds to five 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 was in complete remission after infusion and continued remission for 6 months;

3.
As of the data cutoff, 11 patients are still under study
.
Among the 8 responders, 5 patients still responded, and the remaining patients had no progression for more than 24 weeks
.

In addition, MAGE-A4 tumor antigen has a TCR-T technology afamitresgene autoleuel (afami-cel, formerly known as ADP-A2M4), which is used in a variety of solid tumor types, including synovial sarcoma, head tumor and cervical cancer, and has been used in lung and lung cancer.
Achieved relief
.
Many patients have experienced long-term responses, which means that this new emerging technology based on tcr is a new hope for smashing solid tumors in the future
.

Links to related articles: TCR-T therapy is emerging! The "leader" who challenges refractory solid tumors has begun in the middle and late stages of liver cancer!

All in all, compared with CAR-T, TCR-T has the advantage of higher safety.
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 patients with high expression of the corresponding specific protein and matching type can be used, otherwise there will be no effect
.

In addition to the cellular immunotherapy mentioned above, there is also CTL therapy (using the protein specific to cancer cells that are missing or missing in normal cells as a bait, and selecting "one in a million" in the peripheral blood that can truly fight cancer.
Cell)
.
Dendritic cell vaccine (a group of heterogeneous immune cells with the strongest antigen presentation function, providing the only professional antigen that can activate naive T cells, so it is also called the "sentinel" of the immune system), other cancer vaccines, etc.
Continuously improve technology, and strive to overcome solid tumors as soon as possible
.

The future of cellular immunotherapy is promising, and it is the ultimate weapon to defeat cancer!

According to the latest statistics, compared with patients with advanced lung cancer, gastric cancer, liver cancer and other patients who only receive surgery, radiotherapy, and chemotherapy, adjuvant cell immunotherapy can prolong the survival time of patients and significantly improve the validity 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 required, but chemotherapy or radiotherapy cannot achieve the expected results
   .
   Only supplemented with 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 overall therapeutic effect of tumors
   .
   

3. Cellular immunotherapy is a potential alternative therapy for the treatment of malignant melanoma, kidney cancer and other special types of malignant tumors that are sensitive to chemotherapy and radiotherapy
   .
   

4. Combined cellular immunotherapy can significantly improve the immune system function of tumor patients, help eliminate residual cancer cells and micrometastasis after surgery, and significantly reduce the incidence of local recurrence and distant metastasis
   .
   

5. After the immune cells are expanded in vitro, they 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 patient's survival period 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)