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*For medical professionals only to read and refer to the latest research results
of triple-negative breast cancer immunotherapy.
At the recent 17th National Breast Cancer Conference (CBCC) and the 17th Shanghai International Breast Cancer Forum (SIBCS), Academician Xu Binghe introduced "Cancer Therapy: Development from Targeted Therapy to Immunotherapy" and introduced in detail the research progress
of triple-negative breast cancer (TNBC) immunotherapy.
Breast cancer is one of the most common malignant tumors in women, and triple-negative breast cancer accounts for about 15%~20%
of all breast cancers.
Advanced triple-negative breast cancer has a high degree of malignancy, strong aggressiveness, high recurrence rate, unsatisfactory effect of chemotherapy and targeted therapy, and poor
prognosis.
Therefore, TNBC has been seeking other treatment options
.
Targeted therapy is still the mainstream research and development direction, immunotherapy is rising rapidly, targeted therapy is still the mainstream research and development direction of tumor treatment, and the variety of small molecule targeted drugs under research is much higher than other types of drugs
.
New drugs such as antibody-drug conjugates (ADCs) and bispecific antibodies are also emerging
.
At the same time, in recent years, immunotherapy has risen
rapidly with its advantages of strong specificity, safety and effectiveness.
Fig.
1 Status quo of immunotherapy drugs with different mechanisms (Source: Academician Xu Binghe Conference Courseware)
Tumor immunotherapy is to stimulate and enhance the body's immune function or regulate the body's immune response with the role of biological agents, so as to achieve the purpose
of treating tumors.
Cytotoxic T cells are a key factor for
the immune system to kill tumors.
Since 1988, when tumor-infiltrating lymphocytes (TILs) + interleukin 2 (IL-2) were first verified to be effective in melanoma patients, a series of studies have greatly promoted the development and clinical application
of immunotherapy.
At present, immunotherapy has been recognized as the fifth pillar of oncology treatment, alongside surgery, chemotherapy, radiation therapy and targeted therapy
.
3 major classes of immunotherapy drugs Immunotherapy drugs are mainly divided into 3 categories: immune checkpoint inhibitors, cell/gene therapy and tumor vaccines
.
Fig.
2 Tumor immunotherapy targets and drugs (Source: Academician Xu Binghe Conference Courseware) 1.
Immune checkpoint inhibitors:
PD-1/PD-L1 inhibitors and CTLA-4 inhibitors
PD-1/ The PD-L1 pathway is now recognized as a critical checkpoint
in the immune response of many different cancers.
PD-1/PD-L1 inhibitors monotherapy or in combination with CTLA-4 inhibitors, combined chemotherapy or targeted therapy have become the first-line standard treatment
for metastatic melanoma, lung cancer, kidney cancer, liver cancer, head and neck tumors and triple-negative breast cancer.
■Immunotherapy IMpassion 130 for advanced triple-negative breast cancer is the first successful immunotherapy
study
against TNBC.
Studies have shown clinical benefit
of using atecilizumab plus albumin-bound paclitaxel as first-line therapy in patients with PD-L1-positive unresectable, locally advanced, or metastatic TNBC.
The IMpassion 130 study opens up new hope for immunotherapy, providing new treatment options and benefit opportunities
for TNBC patients.
Fig.
3 IMpassion 130 research (source Xu Binghe Academician Conference courseware)
but the subsequent IMpassion 131 research did not reach the primary research endpoint
.
And the difference between IMpassion 131 and IMpassion130 studies is that the combination partner of atezolizumab is replaced by paclitaxel from albumin paclitaxel to paclitaxel, and the potential cause needs to be further explored
.
The results of translational immunotherapy in advanced triple-negative breast cancer suggest that the spatiotemporal dynamics of tumor invasion immunity in immunocombination therapy:
Leif W.
Professor Ellisen commented, "This work is the largest single-cell omics study on TNBC immunotherapy-related tumor microenvironment in the world so far, which provides a reliable data basis
for in-depth understanding of the spatiotemporal dynamic changes of TNBC tumor microenvironment and the interaction mechanism of drugs in immune combination therapy.
"
2.
Cell therapy and gene therapy At present, the research that has attracted wide attention in cell therapy and gene therapy includes the following: Chimeric antigen receptor T cell (CAR-T) therapy
:
2010, CD19 CAR-T was used for the first time in case reports of lymphoma patients and verified the efficacy
.
In August 2017, the first CD19 CAR-T drug was approved by
the FDA.
China's research experience in CAR-T ranks in the forefront of the world, and 2 CAR-T products have been approved for marketing
.
Adoptive T cell (TCR-T) therapy: Clinical trials focused on melanoma, synovial sarcoma, liposarcoma, esophageoma, hematologic tumors
.
TIL cell therapy: clinical trials mainly focus on melanoma, but there are also other solid tumors, such as sarcoma, non-small cell lung cancer, etc
.
In addition, there are also individual reports of TIL cells for breast cancer treatment, and the combination of transfected TIL cells combined with interleukin-2 and immune checkpoint inhibitors has achieved complete and sustained remission in patients with metastatic breast cancer for more than
22 months.
Fig.
4 TIL cell therapy for breast cancer cases (source Xu Binghe conference courseware)
NK cell therapy: shown good efficacy
in clinical trials of hematological tumors.
Efficacy in solid tumors still needs to be proven
in practice.
CIK cell/DC-CIK cell therapy: demonstrated efficacy
in hematologic tumors, liver cancer and renal cell carcinoma.
Attacks normal cells rarely and side effects such as graft-versus-host disease (GVHD) are fewer
.
3.
Tumor vaccines include dendritic cell vaccines, peptides, DNA, RNA vaccines
and oncolytic cell viruses (treatment methods that kill tumors by selectively infecting tumor cells by viruses), Among them, the containment virus has received more attention
.
From 2000 to 2020, a total of 97 oncolytic virus-related clinical trials
including breast cancer were conducted.
At the end of the conference on the thinking and prospect of immunotherapy, Academician Xu Binghe said that he believed that through the joint efforts of basic transformation and clinical researchers, immunotherapy will become tumor treatment.
Including one of the most important effective means of
breast cancer treatment.
And the development of immunotherapy research has brought us some thoughts:
The future direction of immunotherapy includes at least 5 aspects:
of triple-negative breast cancer immunotherapy.
At the recent 17th National Breast Cancer Conference (CBCC) and the 17th Shanghai International Breast Cancer Forum (SIBCS), Academician Xu Binghe introduced "Cancer Therapy: Development from Targeted Therapy to Immunotherapy" and introduced in detail the research progress
of triple-negative breast cancer (TNBC) immunotherapy.
Breast cancer is one of the most common malignant tumors in women, and triple-negative breast cancer accounts for about 15%~20%
of all breast cancers.
Advanced triple-negative breast cancer has a high degree of malignancy, strong aggressiveness, high recurrence rate, unsatisfactory effect of chemotherapy and targeted therapy, and poor
prognosis.
Therefore, TNBC has been seeking other treatment options
.
Targeted therapy is still the mainstream research and development direction, immunotherapy is rising rapidly, targeted therapy is still the mainstream research and development direction of tumor treatment, and the variety of small molecule targeted drugs under research is much higher than other types of drugs
.
New drugs such as antibody-drug conjugates (ADCs) and bispecific antibodies are also emerging
.
At the same time, in recent years, immunotherapy has risen
rapidly with its advantages of strong specificity, safety and effectiveness.
Fig.
1 Status quo of immunotherapy drugs with different mechanisms (Source: Academician Xu Binghe Conference Courseware)
Tumor immunotherapy is to stimulate and enhance the body's immune function or regulate the body's immune response with the role of biological agents, so as to achieve the purpose
of treating tumors.
Cytotoxic T cells are a key factor for
the immune system to kill tumors.
Since 1988, when tumor-infiltrating lymphocytes (TILs) + interleukin 2 (IL-2) were first verified to be effective in melanoma patients, a series of studies have greatly promoted the development and clinical application
of immunotherapy.
At present, immunotherapy has been recognized as the fifth pillar of oncology treatment, alongside surgery, chemotherapy, radiation therapy and targeted therapy
.
3 major classes of immunotherapy drugs Immunotherapy drugs are mainly divided into 3 categories: immune checkpoint inhibitors, cell/gene therapy and tumor vaccines
.
Fig.
2 Tumor immunotherapy targets and drugs (Source: Academician Xu Binghe Conference Courseware) 1.
Immune checkpoint inhibitors:
PD-1/PD-L1 inhibitors and CTLA-4 inhibitors
PD-1/ The PD-L1 pathway is now recognized as a critical checkpoint
in the immune response of many different cancers.
PD-1/PD-L1 inhibitors monotherapy or in combination with CTLA-4 inhibitors, combined chemotherapy or targeted therapy have become the first-line standard treatment
for metastatic melanoma, lung cancer, kidney cancer, liver cancer, head and neck tumors and triple-negative breast cancer.
■Immunotherapy IMpassion 130 for advanced triple-negative breast cancer is the first successful immunotherapy
study
against TNBC.
Studies have shown clinical benefit
of using atecilizumab plus albumin-bound paclitaxel as first-line therapy in patients with PD-L1-positive unresectable, locally advanced, or metastatic TNBC.
The IMpassion 130 study opens up new hope for immunotherapy, providing new treatment options and benefit opportunities
for TNBC patients.
Fig.
3 IMpassion 130 research (source Xu Binghe Academician Conference courseware)
but the subsequent IMpassion 131 research did not reach the primary research endpoint
.
And the difference between IMpassion 131 and IMpassion130 studies is that the combination partner of atezolizumab is replaced by paclitaxel from albumin paclitaxel to paclitaxel, and the potential cause needs to be further explored
.
The results of translational immunotherapy in advanced triple-negative breast cancer suggest that the spatiotemporal dynamics of tumor invasion immunity in immunocombination therapy:
- Paclitaxel selectively damages underlying tumor-reactive T cells and DC cells, impairing anti-tumor immunity, thereby affecting the efficacy
of atelizumab combination therapy. - Tumor T cells + B cells can predict the efficacy
of immune combination therapy. - Expansion of follicular B cells, lymphoid tissue-induced cells, CXCL13+ T cells, and traditional type 1 dendritic cells (cDC1) was seen in the combination therapy effective group, indicating their importance
in anti-tumor immunity. - The leukocytes in the peripheral blood somewhat reflect the immune characteristics
of the tumor microenvironment (TME).
Leif W.
Professor Ellisen commented, "This work is the largest single-cell omics study on TNBC immunotherapy-related tumor microenvironment in the world so far, which provides a reliable data basis
for in-depth understanding of the spatiotemporal dynamic changes of TNBC tumor microenvironment and the interaction mechanism of drugs in immune combination therapy.
"
2.
Cell therapy and gene therapy At present, the research that has attracted wide attention in cell therapy and gene therapy includes the following: Chimeric antigen receptor T cell (CAR-T) therapy
:
2010, CD19 CAR-T was used for the first time in case reports of lymphoma patients and verified the efficacy
.
In August 2017, the first CD19 CAR-T drug was approved by
the FDA.
China's research experience in CAR-T ranks in the forefront of the world, and 2 CAR-T products have been approved for marketing
.
Adoptive T cell (TCR-T) therapy: Clinical trials focused on melanoma, synovial sarcoma, liposarcoma, esophageoma, hematologic tumors
.
TIL cell therapy: clinical trials mainly focus on melanoma, but there are also other solid tumors, such as sarcoma, non-small cell lung cancer, etc
.
In addition, there are also individual reports of TIL cells for breast cancer treatment, and the combination of transfected TIL cells combined with interleukin-2 and immune checkpoint inhibitors has achieved complete and sustained remission in patients with metastatic breast cancer for more than
22 months.
Fig.
4 TIL cell therapy for breast cancer cases (source Xu Binghe conference courseware)
NK cell therapy: shown good efficacy
in clinical trials of hematological tumors.
Efficacy in solid tumors still needs to be proven
in practice.
CIK cell/DC-CIK cell therapy: demonstrated efficacy
in hematologic tumors, liver cancer and renal cell carcinoma.
Attacks normal cells rarely and side effects such as graft-versus-host disease (GVHD) are fewer
.
3.
Tumor vaccines include dendritic cell vaccines, peptides, DNA, RNA vaccines
and oncolytic cell viruses (treatment methods that kill tumors by selectively infecting tumor cells by viruses), Among them, the containment virus has received more attention
.
From 2000 to 2020, a total of 97 oncolytic virus-related clinical trials
including breast cancer were conducted.
At the end of the conference on the thinking and prospect of immunotherapy, Academician Xu Binghe said that he believed that through the joint efforts of basic transformation and clinical researchers, immunotherapy will become tumor treatment.
Including one of the most important effective means of
breast cancer treatment.
And the development of immunotherapy research has brought us some thoughts:
- More accurate predictive markers are needed to identify the beneficial population for precision treatment
. - Reasonable clinical research endpoints should be determined during clinical research
. - Emphasis is placed on the management of adverse reactions (as immune-related adverse effects may affect all organs).
- It is necessary to find a more effective combination treatment plan: while killing the tumor, it further increases the efficacy
by increasing exposure, presenting antigens, avoiding escape, etc.
The future direction of immunotherapy includes at least 5 aspects:
- more predictive markers;
- Reasonable joint schemes;
- to identify the mechanism of immunosuppressant resistance;
- strategies to promote more inflammation and immune response in tumors;
- Precision immunotherapy
.
