Dr. Zheng Biao, Chief Scientific Officer of Jingpharm: Combination Therapy Emerges as the New Frontier in Tumor Immunotherapy

Tumor immunotherapy has achieved breakthrough progress in cancer treatment, but the therapeutic efficacy remains unsatisfactory. Combination therapy is an ideal and necessary approach for tumor immunotherapy.

On October 17, at the 2019 Yangtze River Delta Innovative Pharmaceutical Sciences Forum, Dr. Zheng Biao delivered a speech themed “Frontiers in R&D of Tumor Immunotherapy.” VCBeat has compiled and edited the highlights of his presentation.

Dr. Zheng Biao, Chief Scientific Officer of Genfleet Therapeutics

William Coley, an American surgeon, was a pioneer in tumor immunotherapy. On July 29, 1908, The New York Times reported that Dr. Coley used bacteria causing erysipelas to treat tumors.

While reviewing medical records left by his mentor, Dr. Coley was drawn to the case of a patient whose osteosarcoma had recurred several times before he developed a bacterial infection. Remarkably, following the infection, the patient’s tumor vanished. This observation led Dr. Coley to consider using bacteria as a treatment for tumors.

By 1908, over a period of 15 years, Dr. Coley had treated 430 patients using this method, with 150 patients being cured. By 1933, he had treated more than 1,000 patients in total, half of whom experienced disease remission.

However, due to the limitations of the era, the bacterial preparations and treatment regimens at the time were highly complex, making it impossible for hospitals to widely replicate Dr. Coley’s tumor immunotherapy approach. Furthermore, with the rise of radiation therapy, this method gradually fell into decline. It was not until 1975 that tumor immunotherapy began to regain attention.

Since 1908, the field of cancer immunotherapy has seen continuous advancements over more than a century, but true breakthroughs have occurred only since the 1990s. For instance, in 2010, the first cellular vaccine for treating prostate cancer received FDA approval; in 2011, a CTLA-4 monoclonal antibody was approved by the FDA; and in 2014, Opdivo and Keytruda were approved for the treatment of acute lymphoblastic leukemia. These milestones demonstrate the rapid development of cancer immunotherapy in recent years.

Tumors can be broadly classified into three categories: the first type exhibits a significant presence of cytotoxic cells locally; the second type features impaired cytotoxic cell function; and the third type lacks cytotoxic cells altogether. PD-1 and PD-L1 antibodies demonstrate optimal therapeutic efficacy against the first category. For the other two types, tailored combination therapy regimens can be designed based on their distinct mechanisms to enhance treatment outcomes.

Why Is Combination Therapy Required for Tumor Immunotherapy?

First, combination therapy can activate the human immune system, broaden the immune response, and promote anti-tumor immunity within the tumor microenvironment. Second, from an individual patient perspective, combination therapy can produce synergistic drug effects, enhancing both the responsiveness and durability of treatment, which is the primary objective of such regimens. Third, combination therapies offer a broader spectrum of activity, enabling the treatment of a wider range of disease types or providing greater selectivity against tumors.

The key to immunotherapy for the second and third types of tumors mentioned above lies in the generation of T cells. Vaccines, chemotherapy, and radiotherapy are all highly effective methods for promoting T-cell production. Combination therapy with CTLA-4 monoclonal antibodies can also be considered to activate T cells and facilitate their infiltration into the tumor microenvironment.

In the past two years, there has been a significant increase in tumor-related immunotherapies. Two years ago, human tumor-associated antigens (TAAs) were the primary targets; now, PD-L1 has gradually become the focal point of attention, indicating a growing emphasis on the specificity of target selection. However, currently, most targets remain concentrated on PD-1 and PD-L1. Target selection remains highly imbalanced, with substantial untapped potential yet to be explored.

From a mechanistic perspective, the process of tumor immunotherapy begins with the release of tumor cell antigens to activate the immune system. Subsequently, the activated immune cells must migrate from lymphoid tissues into the tumor microenvironment. Adequate infiltration of these cells into the tumor microenvironment is essential for them to exert their therapeutic effects, thereby achieving the recognition and elimination of tumor cells.

Based on the different stages of the tumor immunotherapy process, we can design various combination therapy regimens, such as incorporating radiotherapy and chemotherapy to release antigens and enhance therapeutic efficacy. Additionally, different targets can be selected for combination therapy to promote antigen amplification.

From the initial combination of radiotherapy, chemotherapy, and surgery to the current use of combination immunotherapy regimens, these advances have brought hope to cancer treatment. However, most existing combination immunotherapy regimens still involve the concurrent use of CTLA-4 monoclonal antibodies and PD-1 antibodies.

Since immune responses require specific dosages, moderate doses are necessary to trigger a robust immune response. Therefore, different targets can be selected for combination therapy in varying contexts.

Furthermore, scientific research has revealed that the gut microbiota plays a significant modulatory role in cancer therapy. Dysbiosis of the gut microbiota or the absence of specific bacterial strains can compromise the efficacy of PD-1 and PD-L1 antibody treatments. Currently, several companies worldwide are beginning to leverage microbiota-based approaches in combination with tumor immunotherapy.