Yu Jinming: Top 10 Challenges of Cancer Immunotherapy.

Perhaps not well known to many, there are eleven medical revolutions that can be recorded in history, from the discovery of X-rays in Lenchen as early as 1895 to the most recent Immune DC vaccine in 2010, which have two major in common: technological innovation and cross-border integration.
three revolutions in the progress of oncology and internal medicine, followed by cell cycle-based chemotherapy, gene mutation-based targeted drugs, and immunotherapy based on immune escape.
For immunotherapy, on September 20, held the "23rd National Conference on Clinical Oncology and 2020 CSCO Academic Conference" lung cancer special session, Shandong Province Cancer Hospital President Yu Jinming academician believes that it is like that year's penicillin did not solve all the infection problems, but opened a roaring antibiotic revolution in general, immunotherapy, immunotherapy, immunotherapy (IO) will certainly subvert the traditional concept of cancer treatment, cancer treatment revolution.
? It has to be admitted that immunotherapy is indispensable in the treatment of non-small cell lung cancer, but it also faces ten practical challenges.
1. Tumor heterogeneity is a challenge in precision immunotherapy Where tumor heterogeneity exists between patients, between tumors and within tumors, and can be subdivided into three levels: DNA, RNA, and protein.
mainly due to the differences in micro-environment and other factors, in recent years, the study explores the drivers of tumor immunosuppressive diversity.
2. Primary, adaptive and access to drug resistance is the greatest challenge, both endogeneic and exogenetative, and has not yet been clarified.
At present, the clinical mainly face three practical problems of primary resistance: tumor internal causes of drug resistance, or no related antigens and antigens less, not recognized by the immune system;
you do? Immunotherapy should be combined with clump heating, i.e. IO-X, X including chemotherapy, surgical treatment, radiotherapy, vascular targeted therapy, other immunotherapy and even EGFR-TKI (the skin growth factor inhibitor-tyrosine kinase inhibitor), the purpose is to delay or overcome drug resistance and improve efficacy, early efficacy.
3. The prognostic evaluation of the relationship between multiple biomarkers and prognostics and the realization of individualized precision immunomarkers is not yet uniform, and it is now known that the higher the PD-1 expression, the higher the long-term survival, but 75% of the non-long-term benefits come from patients with effective early treatment;
we know that PD-1 high expression is good for immunotherapy, but can radiotherapy be combined with immunotherapy? It's completely different! Instead, PD-1 expressionists (1% to 49%) benefited more.
this requires clinicians to continue to explore immunotherapy efficacy and immune damage through histology, liquid biopsy, molecular imaging individualization.
4. The limited clinical immuno-transformation capacity of preclinical models The current preclinical models are based on mice, which is completely different from the development of tumors in the human body for more than a decade and does not fully reflect the real immune situation of the human body.
, genetically engineered mice have problems that cannot be solved, such as long-term natural accumulation of cancer mutations in humans.
5. Understanding that tumor immunity to a particular organ is not sufficient for tumor growth and metastasis is related to the microenceptic environment of its organs, and that there are differences in immune sensitivity, such as poor immunity of the liver and bone marrow to tumors, while lungs, skin, lymph nodes, etc. are more beneficial to tumor immunity.
, organ-specific treatment is generally not taken into account in the clinical treatment of tumors.
Checkmate 017/057 study showed that Nivolizumab's second-line treatment of lung cancer was successful, while the Checkmate-143 study confirmed that it failed to improve patient survival by failing to respond to relapsed cerebroglioblastoma.
6. How to find a better evaluation criterion for immunotherapy is challenged By the fact that immunotherapy has a good list of toxicity that is far more complex than other chemotherapy and targeted treatments, it is difficult or almost impossible to predict.
, RECIST v1.1 is the most widely used in clinical practice, but its ability to assess the following three issues is limited.
false progression: after immunotherapy lesions increase or new lesions appear, biopsies confirmed necrosis or inflammatory cell immersion, and then the tumor load decreased.
hyper-progress; increase in volume between the first evaluation and pre-treatment after immunotherapy by 50% compared to volume; and TGKR,2 (post-treatment/pre-treatment tumor growth dynamics ratio); and the rate of reported abroad was 4% to 29%, higher than traditional chemotherapy.
efficacy separation: the performance of ORR, PFS, mesos, annualized OS and other evaluation indicators separation, two separation response refers to the tumor after treatment, part of the tumor volume increase, two parts of the tumor lesions volume reduction phenomenon.
7.5% in patients with non-small cell lung cancer, and its prognostication was better than mere progress, radiotherapy could be considered.
In recent years, researchers have been actively looking for markers to predict super-progression after immunotherapy chemotherapy, and now believe that three variables, older, radiotherapy-like in-zhao, and genomic changes (MDM2 amplification and EGFR mutations), may indicate hyper-progression.
7. The timing of the consolidation and maintenance of immunotherapy applications has not yet been determined8. O-X: The purpose of the immune union to overcome the challenge of the drug-resistant mechanism is to avoid the slow immune efficacy, the early intersection of the survival curve, and improve the immune efficacy.
many anti-tumor immune nodes, the best immunotherapy in the future is not a single therapy, the combination of treatment is still not enough to overcome metastasis non-small cell lung cancer resistance.
but the multi-pronged immune union, the mechanism by which multiple links can be regulated to overcome drug resistance is still unclear.
So, the immune union is not a "messy stew" is not a simple "arrangement combination", but the need for sequence, need fire, need ratio, need to add accurate combination and optimization: First, to achieve the efficacy of 1 plus 1 plus 2, rather than cost and toxicity add up;
, how does the time and order of application of different drugs vary during immunotherapy? Radiotherapy plus CTLA-4: Immune and then radiotherapy, because it acts on the lymph nodes, activates CD4-T and inhibits Treg to increase the release of PD-L1; D-1 and PD-L1 act directly on the tumor, so it is recommended to use at the same time or later; radiotherapy and OX40: radiotherapy and then immunity, because OX40 astiotherapist radiotherapy can be used to maximize the induction of CD8-T cell activity.
9. Chemotherapy works fast in value-added, targeted on the expression cells of the subject, immunity to normal tissue damage is not clear immune toxicity, if only immune reactions and allergic reactions, the application of hormones can solve the problem.
clinically there are still serious complications, so there may be off-target and other causes.
toxic reaction mainly attacks the four organs, they are the heart, thyroid gland, small intestine and pituitary gland, the main fatal side effects are myocarditis, pneumonia, enteritis, hepatitis, its damage mechanism is not the same, the degree of various drugs are also very different.
10. The effects of steroids and antibiotics on immunotherapy and the challenges of clinical oncologists require careful measurement of the pros and cons of the application of steroids and antibiotics in immunotherapy, which must not be used in the long term, in large quantities and in a broad spectrum, so as not to cause greater harm to patients.
conclusion: "Immune therapy" is bright, the road is tortuous, but to innovate, to integrate, to transform.
what is the future of cancer cure, is "immune combination", still need to be in the immuno combination of chemotherapy and other treatments, multi-target and stronger target immunity, to explore the immunotherapy predictive markers of three aspects of strength forward.
Xin Xiaoxuan Source: Medical Forum Network Copyright Notice: All text, images and audio and video materials on this website that indicate "Source: Mets Medicine" or "Source: MedSci Original" are owned by Metz Medicine and may not be reproduced by any media, website or individual without authorization, and shall be reproduced with the words "Source: Mets Medicine".
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