Researching Cancer Immunity Targets
Genentech is actively exploring the potential of disrupting the immunosuppressive processes that promote tumor growth, and bolstering the immune system's power to fight cancer.
The immune system plays a crucial role in protecting the body against cancer by recognizing and destroying cells it perceives as foreign. Cancer immunity strategies aim to restore the immune system's abilities to mobilize an antitumor immune response. Some strategies aim to override the mechanisms that prevent T cells from mounting an immune response. Some aim to negate the mechanisms that prevent T cells from infiltrating the tumor microenvironment. Others seek to stimulate an immune response, thereby strengthening detection and destruction of newly transformed or developing tumors, and reducing the likelihood of further tumor growth and metastases.1,2
Since multiple immune inhibitory mechanisms are often present concurrently, Genentech aims to evaluate and develop diverse combination strategies to optimize the antitumor immune response.3
Click on the image below to learn more.1,2,4,5
Immune phenotypes characterize the critical points at which cancer immunity fails
Genentech scientists believe that human cancers can be characterized by 3 distinct immune phenotypes. These phenotypes describe the level of T-cell presence and activity in the tumor microenvironment, and help to inform strategies for initiating or restoring the antitumor immune response in patients with cancer.2-5
- Immune desert
- Immune excluded
The classification of these 3 immune phenotypes provides a foundation for tailoring the right approach to the right patient, and is fundamental to supporting the development of novel combination strategies.
In this immune phenotype, there is a lack of pre-existing immunity.
- The generation of tumor-specific T cells is the rate-limiting step. Therefore, single-agent PD-L1/PD-1 blockade is unlikely to elicit T-cell–mediated immunity
- Strategies aim to elicit T-cell immunity through increased T-cell priming, recruitment, and redirection by enhancing antigen generation and presentation
- Genentech is investigating the role of multiple immune mechanisms and targets in combination approaches to elicit T-cell immunity in the immune desert phenotype, including 6-8
In this immune phenotype, there is some pre-existing immunity, but T cells are at the periphery of tumors.
- Antitumor T cells accumulate at the tumor site but fail to efficiently infiltrate the tumor microenvironment. T cells are rendered ineffective by their inability to infiltrate the tumor stroma. Therefore, the rate-limiting step is T-cell penetration through the tumor stroma
- Strategies aim to infiltrate the tumor by overcoming the stromal barrier, recruiting T cells to the tumor, or redirecting and engaging T cells
- Genentech is investigating the role of multiple immune mechanisms and targets in combination approaches to promote T-cell infiltration in the immune excluded phenotype, including 6,7,9
In this immune phenotype, pre-existing immunity is present at the tumor site.
- Antitumor T cells infiltrate the tumor but are not functioning properly. Therefore, although single-agent PD-L1/PD-1 blockade can elicit T-cell response, it is not assured
- Strategies aim to kill* tumor cells by further invigoration of T-cell activity
- Genentech is investigating the role of multiple immune mechanisms and targets in combination approaches to further invigorate T-cell activity in the inflamed phenotype, including 6,7,9,10
*Tumor cell killing by CD8+ T cells.
Cancer Immunity Cycle>
Establishing the scientific foundation of cancer immunity research1,5
Based upon years of fundamental research, Genentech scientists have identified a unifying framework called the “cancer immunity cycle”—a 7-step process that describes how healthy immune systems can recognize and eradicate cancer.
A patient with cancer may experience disruption at one or more steps of the cancer immunity cycle. As a result, a multitarget combination or sequencing strategy may be required to initiate or reinitiate a self-sustaining cycle of cancer immunity.
With this scientific framework, Genentech is able to spearhead a more systematic approach to cancer immunity research—with the aim of a more personalized strategy for patients with cancer.
Step 1: Antigen release1,5
The cycle starts with antigen release. Neoantigens are released as a result of tumorigenesis and captured by dendritic cells for processing. Additional immunogenic signals may include proinflammatory cytokines and factors released by dying tumor cells or by the gut microbiota.
Step 2: Antigen presentation1,5
The next step in the process is antigen presentation. Dendritic cells present to T cells the captured antigens on major histocompatibility complex (MHC) I and MHC II molecules.
Step 3: Priming and activation1,5
The presentation of antigens on MHC I and MHC II leads to priming and activation of effector T-cell responses against the cancer-specific antigens that are perceived to be foreign. The nature of the immune response is determined at this stage by the ratio of T-effector cells versus T-regulatory cells.
Step 4: T-cell trafficking1,5
Now that the antitumor T cells have been activated, they enter the bloodstream and travel through the body to the tumor bed.
Step 5: T-cell infiltration1,5
When the activated antitumor T cells arrive at a location where a tumor cell is present, they infiltrate the tumor.
Step 6: T-cell recognition1,5
Now the T cells are in the tumor microenvironment. The activated effector T cells specifically recognize and bind to cancer cells through the interaction between their T-cell receptor (TCR) and their cognate antigen bound to MHC I.
Step 7: T-cell–mediated killing* of tumor cells1,5
The last step in the cycle is T-cell–mediated killing* of tumor cells. In this important step, the activated effector T cells kill* their target tumor cells. The killing of the cancer cells releases additional tumor-associated antigens, increasing the breadth and depth of the immune response in subsequent revolutions of the cycle.
*Tumor cell killing by CD8+ T cells.
- Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. PMID: 23890059
- Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27:1492-1504. PMID: 27207108
- Gajewski TF. The next hurdle in cancer immunotherapy: overcoming the non—T-cell—inflamed tumor microenvironment. Semin Oncol. 2015;42:663-671. PMID: 26320069
- Hegde PS, Karanikas V, Evers S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res. 2016;22:1865-1874. PMID: 27084740
- Chen DS, Mellman I. Elements of cancer immunity and the cancer—immune set point. Nature. 2017;541:321-330. PMID: 28102259
- Roche first-quarter results 2019 presentation. https://www.roche.com/dam/jcr:f03df0f2-852c-47a5-9924-343bfb239c37/en/irp190417.pdf. Accessed April 18, 2019.
- Data on file, Roche imCORE 2016 presentation. Genentech, Inc and Hoffman-La Roche, Ltd.
- Brea EJ, Oh CY, Manchado E, et al. Kinase regulation of human MHC class I molecule expression on cancer cells. Cancer Immunol Res. 2016;4:936-947. PMID: 27680026
- Mellman I. Developments in cancer immunity. Presented at: Credit Suisse 26th Annual Healthcare Conference 2017; November 7-9, 2017; Scottsdale, AZ. https://www.roche.com/dam/jcr:e241442b-c7f7-4645-96b9-73bc2287081f/en/irp20171107.pdf. Accessed January 31, 2019.
- Voron T, Colussi O, Marcheteau E, et al. J Exp Med. 2015;212:139-148. PMID: 25601652