How to interpret the development of tumor immunity from the therapeutic field?

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How to interpret the development of tumor immunity from the therapeutic field?

Cytokines

Early discovery in the field of tumor immunotherapy is the role of cytokines. Cytokine therapy has a glorious past. It was the first immunotherapy drug approved by the FDA for tumors.

For example, IFNα-2a (Roferon-A) and IFNα-2b (Intron-A) were approved for multiple treatments in 1986.

A type of lymphoma, high-dose IL-2 (Proleukin) was approved for metastatic melanoma and kidney cancer in 1992 and 1998.

In 1976, Robert Gallo of the NCI Tumor Cell Biology Laboratory used PHA to stimulate lymphocytes to produce conditioned medium to cultivate bone marrow cells, and 90% of T cells survived for up to 9 months.

Prior to this, primary T cells could not be cultured in vitro, which was a huge technical bottleneck for the development of immunology.

This unpurified component is called T cell growth factor, or IL-2.

In 1983, Junji Hamuro and others of the Cancer Research Center of the Japan Cancer Research Foundation cloned the IL-2 gene and completed the sequencing work.

And conducted research in mouse models, and found that it can promote the regression of metastatic malignant tumors such as syngeneic sarcoma and melanoma.

This ultimately made IL-2 the first cancer immunotherapy drug in humans.

However, because of its short half-life, narrow therapeutic window, large toxic and side effects, and simultaneous stimulation of Treg activation, its clinical use is limited.

Checkpoint inhibitor

Soon after IL-2 was approved, checkpoint inhibitors came to the fore in cancer research.

In 1987, scientists discovered that there is an immunoglobulin on the surface of CD4+ or CD8+ T cells, called cytotoxic lymphocyte antigen 4 (CTLA-4).

The discovery of CTLA-4 will be a checkpoint inhibitor for all future The discovery paved the way.

J Ames P. Dr. Allison was the first to identify and clarify one of the immune function of CTLA-4 scientists.

In 1996, Allison confirmed in mice that anti-CTLA-4 monoclonal antibodies can promote the immune system to kill tumors, so Ipilimumab was born in Dr. Allison’s laboratory.

In 1999, the biotechnology company Medarex obtained a patent for this antibody.

Dr. Allison and Dr. Jedd D. Wolchok, a melanoma clinical expert, jointly developed the anti-CTLA-4 antibody developed by Mederax to treat melanoma.

After unremitting efforts, ipilimumab was approved for the treatment of metastatic melanoma in 2011, becoming the first checkpoint inhibitor for clinical treatment.

By directly blocking CTLA-4, ipilimumab opens up a way for downstream T cell activation, proliferation and ultimate tumor destruction.

After the discovery of CTLA-4, Ishida et al. discovered programmed death receptor-1 and programmed death ligand-1 (PD-1/PD-L1) in 1992.

At present, PD-1/PD-L1 inhibitors have become the cornerstone of the field of tumor immunotherapy.

There are a number of PD-1 inhibitors on the market, including nivolumab, pembrolizumab and cemiplimab, as well as the PD-L1 inhibitors atezolizumab, avelumab and durvalumab.

At present, there are more than 2000 trials of PD-1/PD-L1 inhibitor combination drugs for various malignant tumors in progress.

However, the treatment of PD-1 is still only 10-30% of patients showing long-term, long-lasting response, most of the population lacks response, and acquired drug resistance and immune-related adverse events (IRAE) are also huge obstacles.

One of the mechanisms to overcome the limitations of PD-1 treatment is to target other immune checkpoints related to the tumor microenvironment, such as LAG-3, TIGIT, TIM-3, VISTA, B7-H3, ICOS and BTLA, these new types of immune checks The point is a feasible and promising option for the treatment of solid tumors, and a number of clinical trials are currently being actively studied.

In addition, the combination therapy of checkpoint inhibitors, such as simultaneous blockade of CTLA-4 and PD-1, can inhibit tumor development through different mechanisms.

At present, the FDA has approved the combination of ipilimumab and nivolumab to treat a variety of malignant tumors.

However, increased toxicity is still an obstacle to many combination therapies.

Anti-tumor monoclonal antibody

Kohler and Milsten won the Nobel Prize in Physiology or Medicine in 1984 for their hybridoma technology.

This breakthrough has promoted the development of many anti-tumor monoclonal antibodies and has greatly influenced cancer treatments in the past decades.

Since the first therapeutic antibody entered the clinic in 1986, therapeutic antibodies have developed rapidly.

So far, the FDA has approved nearly a hundred therapeutic antibody drugs, which have become an important part of modern biomedicine.

Antibodies can interact with immune cells through the Fc domain of antibodies to target and destroy tumors that express specific antigens.

Depending on the type of antibody, this immune cell-antibody interaction can lead to tumor cell death in a variety of ways, including complement-dependent cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis ( ADCP).

Although monoclonal antibodies are currently the mainstream of cancer treatment, there are still many challenges.

Due to the dynamic nature of cancer cells and their persistent mutations, any acquired anti-monoclonal antibody resistance will lead to treatment failure.

Antibody-conjugated drug (ADC) is a very effective strategy.

It couples cytotoxic small molecule drugs to monoclonal antibodies through a reasonably constructed linker, which can selectively deliver effective cytotoxic drugs into tumors.

In 2009 gemtuzumab ozogamicin (Mylotarg) was the first ADC drug approved by the FDA.

At present, the FDA has approved 11 ADC drugs for the market, and hundreds of ADC drugs are in the clinical research phase.

In 2009, kalinomycin, calendula and maytansine were the main cytotoxins used in ADC development. For ten years, these molecules are still being used as payloads to optimize for better stability and hydrophilicity.

New cytotoxic substances have also been developed, such as PBDs, ducamycin and camptothecin derivatives.

Antibody engineering has also made considerable progress in the past 10 years, allowing more site-specific couplings and improving the uniformity and stability of ADCs.

The new second-generation and third-generation ADCs have entered the clinic in order to obtain better therapeutic effects and safety.

Dozens of biological coupling technologies based on cysteine residues, unnatural amino acids or molecular engineering models have also been verified in preclinical studies.

In addition, more tumor-specific antigen targets and the release mechanism of cytotoxic drugs in tumors have enabled ADC to achieve explosive development, and ADC drugs have entered the golden age.

CAR-T cell therapy

Chimeric antigen receptor (CAR) T cell therapy has brought revolutionary changes to the treatment of hematological malignancies.

In the early 1990s , Israeli scientist Eshhar and Hwu in Rosenberg’s laboratory successfully constructed three chimeric antigen receptors for different cancer targets using antibody-derived single-chain antibody fragment scFv, the first-generation CAR-T Thus was born.

Afterwards, CAR-T technology has undergone one generation and two generations of development, solving the problems of scale and production technology, and CAR-T has finally begun to enter the market.

The first CD19-targeted CAR-T cell (Kymriah) was approved for relapsed refractory acute lymphoblastic leukemia in 2017.

In the past seven years, more and more clinical trials have appeared in China to evaluate the safety and effectiveness of CAR-T therapy.

Second only to the United States, China is the main force in CAR-T therapy research, contributing about 33% of global clinical trials.

So far, the China National Medical Products Administration (CNDA) has approved more than 10 CAR-Ts products for clinical trials, including CAR-Ts targeting CD19, BCMA and glypican3 (GPC3).

Currently, two CAR-T therapies targeting CD19 have been approved for marketing in China.

Although CAR-T cell therapy has been successful in hematological tumors, it still has many limitations in solid tumors.

A key factor of this limitation is the tumor-associated antigen heterogeneity of solid tumor cells.

Another difficulty of solid tumors is the ability of CAR-T cells to penetrate through the vascular system and eventually reach the target tumor.

In addition, although CAR-T cells have high potential, they also have obvious toxicity, including severe cytokine release syndrome (CRS) and severe neurotoxicity. In addition, the high cost of treatment also limits the wide application of CAR-T cells.

At present, new concepts and strategies for CAR-T cell therapy for solid tumors are emerging.

These advances include better target selection through the transfer of tumor-associated antigens to personalized tumor-specific neoantigens, enhancement of T cell trafficking by breaking the matrix barrier, and depletion of TME by targeting the immunosuppressive mechanism in TME.

T cell regeneration. In addition, CAR-NK cell therapy is also a promising research field. Compared with CAR-T cells, CAR-NK cells have their own unique advantages and are expected to provide better efficacy and safety.

Bispecific antibody

Although monoclonal antibodies have become the mainstay of cancer treatment, bispecific antibodies are gradually becoming an important and promising component of next-generation therapeutic antibodies because they can target two epitopes in tumor cells or tumor microenvironment at the same time.

Most of the double antibodies currently under development are designed to connect tightly with tumor cells through immune cells, especially cytotoxic T cells, to form an artificial immune synapse, which ultimately leads to selective attack and lysis of targeted tumor cells. Blinatumomab is the first approved bispecific antibody that targets both CD3 and CD19.

It was approved in 2014 for Ph-negative relapsed or refractory B-cell acute lymphoblastic leukemia.

From 1997 to 2020, there were a total of 272 clinical trials related to bsAbs research worldwide. 29% of the studies were initiated by Chinese pharmaceutical companies and institutions, ranking second after the United States.

Global bsAbs clinical trials are mainly concentrated in phase I (n=161), phase I/II, phase II and phase III trials are still very few.

The mechanism of action of BsAbs includes different types. At present, the mechanism of bsAb research in the world is mainly based on T cell-directed therapy, while China’s initiative or participation is mainly based on double immune checkpoint blocking.

Both bispecific antibodies and CAR-T cells are used for T cell-directed immunotherapy, and both methods have their own advantages and disadvantages.

Although CAR-T cells have a better therapeutic effect on hematological malignancies, they are expensive to treat and require additional training.

Compared with CAR-T, bispecific antibodies are “off the shelf”, thus reducing costs and increasing treatment opportunities for many patients.

Both CAR-T cells and double antibodies have side effects, including cytokine release syndrome and neurotoxicity.

Tumor vaccines

With the further understanding of tumor antigen host immunity, vaccine-induced immunotherapy has theoretically become an ideal treatment method.

The National Institutes of Health (NIH) defines tumor vaccines as a series of biological modifiers, which can control infections and resist diseases by activating the immune system in the patient’s body, and divide them into two categories.

One is the preventive type. Similar to the polio vaccine injected as a child, it is used for the prevention of healthy people; the other is a therapeutic type, which strengthens the patient’s immune system to resist tumors and directly fires on the patient’s tumor cells. In fact, it is a type of immunotherapy. form.

Preventive vaccine

There are currently two approved cancer prevention vaccines: human papillomavirus (HPV) vaccine and hepatitis B virus (HBV) vaccine. Both of these vaccines target the HPV16 and HPV18 viruses with cancer-causing potential.

Therapeutic vaccine

The use of vaccines for treatment rather than prevention is quite unique in the field of oncology. Bacille Calmette-Guerin (BCG) has been widely used to treat non-muscular invasive bladder cancer (NMIBC) for 40 years.

The FDA-approved therapeutic cancer vaccines include Sipuleucel-T , a dendritic cell-based vaccine used for mild-symptomatic metastatic castration to combat prostate cancer ; and T-VEC , a HSV-1 derivative in lesions Oncolytic virus vaccine for unresectable recurrent melanoma .

The current research on tumor immunotherapy vaccines is mainly based on personalized vaccines based on neoantigens. Vaccines based on neoantigens rather than traditional TAA have several advantages.

First, neoantigens are only expressed by tumor cells, so they can trigger a true tumor-specific T cell response, thereby preventing damage to non-tumor cells;
second, neoantigens are new epitopes derived from somatic mutations, which may bypass The central tolerance of T cells to their own epitopes induces an immune response to tumors;
in addition, the neoantigen-specific T cell response enhanced by these vaccines persists and generates immune memory, which provides the possibility for long-term prevention of disease recurrence .

Oncolytic virus

Oncolytic virus (OV) therapy is a fairly novel immunotherapy that uses laboratory-engineered viruses to attack and infiltrate malignant cells.

These oncolytic viruses act by directly lysing tumor cells and activating innate and adaptive immune mechanisms.

Since 1949, people have conducted many clinical trials using different types of wild-type non-attenuated viruses.

Soon thereafter, the trend in the OV field evolved into the development of genetically modified viruses that are less pathogenic to humans, such as live attenuated vaccines.

In the past 20-30 years, this transition has continued to the era of using genetically modified viruses for cancer treatment, including the use of viral gene knockout and/or therapeutic transgene knock-in.

In the 21st century, after many clinical trials have obtained positive results, the OV field has gained considerable attention.

So far, four OV drugs have been approved globally.

The first OV is a picornavirus called Rigvir, which is approved in Latvia for the treatment of melanoma, but it has not been widely used.
Secondly, in 2005, China approved an engineered adenovirus called H101 for the treatment of head and neck cancer.
Third, in 2015, the United States and Europe approved another engineered herpes simplex virus (HSV-1) OV called Talimogene Laherparepvec (T-VEC) for the treatment of unresectable metastatic melanoma.
Finally, in 2021, Japan approved a modified herpes simplex virus called DELYTACT for the treatment of brain cancers such as glioblastoma.

Summary

The rapid changes in the field of cancer treatment have highlighted the impact of immunotherapy.

Current efforts include re-study of known treatments in new ways, such as combining checkpoint inhibitors with therapeutic cancer vaccines.

In the era of personalized medicine, key biomarkers and personalized genome sequencing will lead the personalized development of tumor immunotherapy.

Adoptive cell therapy, including CAR-T, CAR-NK, etc., is currently being studied in solid tumors.

However, due to the special characteristics of the solid tumor microenvironment, this is extremely challenging.

Combining checkpoint suppression (such as PD-1/PDL-1 blockade) with CAR-T therapy may prove beneficial and is also under investigation.

The evolution of the field of tumor immunotherapy is accompanied by the continuous expansion of the realization and utilization of new drugs.

In view of the achievements and breakthroughs made in this field, there are still unlimited possibilities in the future.