Researching Cancer Immunity Targets

Our 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.^2,4

Immune phenotypes²

• Immune desert
• Immune excluded
• Inflamed

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.²

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
• We are investigating the role of multiple immune mechanisms and targets in combination approaches to elicit T-cell immunity in the immune desert phenotype, including⁵
  • Generating/releasing/delivering antigens
    • iNeST
    • NY-ESO-1*
    • Oncolytic virus*
    • CAR-T*
    • Chemotherapy*
    • Radiotherapy*
    • MEK
    • HER2
    • BRAF
    • EGFR
    • ALK
    • PARP*
  • Enhancing antigen presentation and T-cell priming
    • CD40
  • Redirecting and engaging T cells
    • CEA CD3
    • CD20 CD3

*External partner.

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
• We are investigating the role of multiple immune mechanisms and targets in combination approaches to promote T-cell infiltration in the immune excluded phenotype, including⁵
  • Recruiting T cells to the tumor
    • iNeST
    • VEGF
    • CXCR4*
  • Addressing the stromal barrier
    • Hyaluronan*
  • Redirecting and engaging T cells
    • CEA CD3
    • CD20 CD3

*External partner.

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
• We are investigating the role of multiple immune mechanisms and targets in combination approaches to further invigorate T-cell activity in the inflamed phenotype, including⁵
  • Invigorating T cells
    • iNeST
    • PD-L1
    • VEGF
    • MEK
    • TIGIT
    • FAP-IL2v
    • A2A^†
    • CD38^†
  • Redirecting and engaging T cells
    • CEA CD3
    • CD20 CD3

*Tumor cell killing by CD8+ T cells.
^†External partner.

Based upon years of fundamental research, our 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, we are able to spearhead a more systematic approach to cancer immunity research—with the aim of a more personalized strategy for patients with cancer.

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.

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.

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.

Now that the antitumor T cells have been activated, they enter the bloodstream and travel through the body to the tumor bed.

When the activated antitumor T cells arrive at a location where a tumor cell is present, they infiltrate the tumor.

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.

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.