The development of tumor immunity from the therapeutic field

1 cytokine

Early discovery in the field of tumor immunotherapy is the role of

In 1976, Robert Gallo of NCI's Tumor Cell Biology Laboratory used PHA-stimulated lymphocyte-producing conditioned medium to culture bone marrow cells, in which 90% of T cells were maintained

In 1983, Junji Hamuro et al.

2 checkpoint inhibitors

Shortly after IL-2 approval, checkpoint inhibitors stood out and came to the forefront

In 1987, scientists discovered an immunoglobulin on the surface of T cells with CD4+ or CD8+, known as cytotoxic lymphocyte antigen 4 (CTLA-4), and the discovery of CTLA-4 paved the way

Dr.

In 1999, the biotechnology company Medarex patented this antibody

Following the discovery of CTLA-4, Ishida et al.

However, only 10-30% of patients treated with PD-1 still exhibit long-term, long-lasting responses, a lack of response in most populations, and acquired drug resistance and immune-related adverse events (IRAEs) are also significant barriers

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

3 Anti-tumor monoclonal antibodies

Kohler and Milesten were awarded the Nobel Prize

Antibodies can interact with immune cells through the Fc domain of the antibody, targeting and destroying tumors

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

Antibody-coupled drugs (ADCs) are a very effective strategy that selectively delivers effective cytotoxic drugs

In 2009, gemmtuzumab ozogamicin (Mylotarg) was the first FDA-approved ADC drug

In 2009, caribromycin, calendula, and methenin were the main cytotoxins

Antibody engineering has also made considerable progress in 10 years, allowing for more site-specific couplings, improving the uniformity and stability
of ADCs.
New second- and third-generation ADCs have entered the clinic in the hope of better treatment outcomes and safety
.
Dozens of bioconjugating techniques based on cysteine residues, unnatural amino acids, or molecular engineering models have also been validated in preclinical studies
.
In addition, more tumor-specific antigen targets and the release mechanism of cytotoxic drugs within tumors led to an explosive development of ADCs, and ADC drugs entered a golden age
.

4CAR-T cell therapy

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of malignancies of the blood system
.

In the early 1990s, Israeli scientist Eshhar collaborated with Hwu in Rosenberg's lab to successfully construct chimeric antigen receptors for three different cancer targets using single-stranded antibody fragments scFv derived from antibodies, and the first generation of CAR-T was born
.
Subsequently, CAR-T technology experienced the development of one generation and two generations, solved the problem of scale and production process, and CAR-T finally began to go to the market
.
The first CD19-targeted CAR-T cells (Kymriah) were approved in 2017 for recurrent refractory acute lymphoblastic leukemia
.

Over the past seven years, more and more clinical trials have emerged in China aimed at evaluating the safety and efficacy of CAR-T therapies
.
Second only to the United States, China is a major force in CAR-T therapy research, contributing about 33% of global clinical trials
.
To date, China's State Drug Administration (CNDA) has approved more than 10 CAR-Ts products for clinical trials, including CAR-Ts
targeting CD19, BCMA and glypican3 (GPC3).
At present, two car-T therapies for CD19 have been approved for marketing
in China.

Although CAR-T cell therapy has been successful in hematological tumors, there are still many limitations in solid tumors, and a key factor in this limitation is the tumor-associated antigen heterogeneity
of solid tumor cells.
Another difficulty with solid tumors is the ability of CAR-T cells to
penetrate through the vascular system and eventually reach the target tumor.

In addition, despite the high potential of CAR-T cells, it also has significant 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 by transferring from tumor-associated antigens to personalized tumor-specific neoantigens, enhancing T cell transport by breaking down the matrix barrier, and regenerating
depleted T cells by targeting immunosuppressive mechanisms in TME.
In addition, CAR-NK cell therapy is also a promising field of research, compared with CAR-T cells, CAR-NK cells have their own unique advantages, is expected to provide better efficacy and safety
.

5bispecific antibodies

While monoclonal antibodies have become the backbone of cancer treatment, bispecific antibodies are becoming an important and promising component
of the next generation of therapeutic antibodies due to their ability to target both epitopes in tumor cells or the tumor microenvironment at the same time.

Most of the dual antibodies currently under development are designed to be tightly connected to tumor cells by immune cells, particularly cytotoxic T cells, thus forming an artificial immune synapse, which ultimately leads to selective attack and lysis
of targeted tumor cells.
Blinatumomab, the first approved bispecific antibody that targets both CD3 and CD19, was approved in 2014 for Ph-negative relapsed or refractory B-cell acute lymphoblastic leukemia
.

From 1997 to 2020, there were 272 clinical trials
of BSAbs studies worldwide.
29 percent of those studies were initiated by Pharmaceutical Companies and Institutions in China, second after the United States
.
Global BSAbs clinical trials are still rarely concentrated in Phase I (n=161), Phase I/II, Phase II and Phase III trials
.
The mechanism of action of BsAbs includes different types
.
At present, the mechanism of international BSAb research is mainly based on T cell-directed therapy, while China's initiation or participation is mainly based on dual immune checkpoint blockade
.

Both bispecific antibodies and CAR-T cells are used for T cell-directed immunotherapy, and both approaches have their pros and cons
.
Although CAR-T cells have better treatment effects on hematologic malignancies, they are expensive to treat and require additional training
.
Bispecific antibodies are "off the shelf" compared to CAR-T, thus reducing costs and increasing the chances of treatment for many patients
.
Both CAR-T cells and diptylexes have side effects, including cytokine release syndrome and neurotoxicity
.

6 tumor vaccines

With the further understanding of tumor antigen host immunity, vaccine-induced immunotherapy has theoretically become an ideal treatment
.
The National Institutes of Health (NIH) defines a tumor vaccine as a series of biological modifiers that control infection and fight off disease by activating the ability of the immune system in the patient's body, and divides it into two categories, one is the preventive type, and the principle is similar to the vaccine injected with polio as a child, which is used for the prevention of healthy groups; The other type is the therapeutic type, which resists the tumor by strengthening the patient's immune system and directly fires the patient's tumor cells, which is actually a form
of immunotherapy.

Preventive vaccines

There are currently two approved cancer prevention vaccines: human papillomavirus (HPV) vaccine and hepatitis B virus (HBV) vaccine
.
Both vaccines target hpv16 and HPV18 viruses with carcinogenic potential
.

Therapeutic vaccines

The use of vaccines for treatment rather than prevention is quite unique in the field of oncology, where bcg is widely used to treat non-muscular invasive bladder cancer (NMIBC) for 40 years
.

The FDA has approved therapeutic cancer vaccines including Sipuleucel-T, a dendritic cell-based vaccine for mild metastatic castration with mild symptoms to fight prostate cancer; and T-VEC, an intrapathic HSV-1-derived oncolytic virus vaccine for unresectable recurrent melanoma
.

At present, the research of tumor immunotherapy vaccines is mainly based on personalized vaccines
based on neoantigens.
Vaccines based on neoantigens rather than traditional TAAs have several points
.
First, neoantigens are expressed only by tumor cells, so a true tumor-specific T cell response can be triggered, thus preventing damage to non-tumor cells; Secondly, the neoantigen is a new epitope derived from somatic mutations, which has the potential to bypass the central tolerance of T cells to their own epitopes, thereby inducing an immune response to tumors; In addition, these vaccine-enhanced neoantigen-specific T cell responses persist and produce immune memory, which opens up the possibility
of long-term prevention of disease recurrence.

7 Oncolytic virus

Oncolytic viruses (OV) treat a fairly novel immunotherapy that utilizes laboratory-engineered viruses to attack and infiltrate malignant cells by directly dissolving tumor cells and activating innate and adaptive immune mechanisms
.

Beginning in 1949, many clinical trials
were conducted using different types of wild-type non-attenuated viruses.
Shortly thereafter, trends in the OV field evolved to develop genetically modified viruses that are less pathogenic to humans, such as live attenuated vaccines
.
Over the past 20-30 years, this shift has continued into the era of using genetically modified viruses for cancer treatment, including the use of viral gene knockout and/or therapeutic transgenic knock-in
.

Entering the 21st century, after many clinical trials have yielded positive results, the OV field has gained considerable attention
.
So far, four OV drugs
have been approved globally.

The first OV, a small RNA virus known as Rigvir, was approved in Latvia for the treatment of melanoma, but was not widely used
.
Second, 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.

brief summary

Rapid changes in the field of cancer treatment highlight the impact of immunotherapy, and current efforts include revisiting 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, this is extremely challenging due to the special characteristics of the solid tumor microenvironment
.
Combining checkpoint suppression (e.
g.
, PD-1/PDL-1 blockade) with CAR-T therapy may prove beneficial is also being studied
.

The evolution of the field of tumor immunotherapy is accompanied by the continuous expansion of the realization and utilization of new drugs, and in view of the achievements and breakthroughs made in this field, there are still infinite possibilities
in the future.