Abstract CN04-02: High priority immunotherapy agents in development to treat and prevent cancer
Authors: Cheever Martin A. “Mac” 
Published: October 2015

The key insight driving the development of effective cancer immunotherapy is that all cancers have mutated proteins, and that many of these mutated proteins are recognizable as foreign by the patient's own T cells. Cancers evolve and become more and more aggressive by continuously accumulating additional mutations. As cancers evolve, T cells co-evolve the capacity to recognize and kill the cancer cells by recognition of the additional mutated proteins.

Unfortunately, cancer cells also co-evolve mechanisms to escape T cell. Many cancer cell escape mechanisms are similar or identical to escape mechanisms exploited by infectious disease pathogens. Equally important for cancer cell escape from immune attack is that the immune system itself is programed to dampen down and limit ongoing T-cell responses. In order to protect the body from excessive T-cell responses and autoimmunity, multiple overlapping and redundant feedback mechanisms limit the size -- and thus effectiveness -- of immune responses, including attacks against cancer.

Fortunately, basic scientists have identified many of the negative influences and have invented and constructed immunotherapeutic agents that counteract the natural/intrinsic programed dampening of T-cell actions that otherwise would allow the subsequent escape of cancer cells from immune attack by T-cells. Accordingly, the rules of cancer therapy are rapidly evolving.

The most important agents are the check-point inhibitors, in particular anti-PD1 and anti-PD-L1. The publication of clinical data with these agents provides a spectacular tipping point towards cancer immunotherapy. In general, subsets of patients with a chronic T cell immune or inflammatory infiltrate are likely to respond to PD1:PD-L1 checkpoint inhibitors whereas patients without an existent immune response or T cell infiltrate are unlikely to respond.

PD1:PD-L1 checkpoint inhibitors are not alone. There are many other agents in development that hit their intended targets and together represent agents to boost a comprehensive variety of mechanisms essential to developing optimal immunotherapy regimens that include amongst others:

• Dendritic cell activators (anti-CD40)

• Dendritic cell growth factors (Flt3L)

• Vaccine adjuvants (CpG, MPL/GLA, poly ICLC, resiquimod)

• T-cell stimulators (anti-OX40, CD137, anti-GITR)

• T-cell growth factors (IL-7, IL-15)

• Immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-LAG3, anti-B7-H4)

• Agents to neutralize or inhibit suppressive cells, cytokines, and enzymes (IDO inhibitor, anti-IL-10, anti-TGF-beta)

The current major task of cancer immunotherapists is to learn how to convert anti-PD1 and anti-PD-L1 non-responders into responders. The major task for employing the same agents for cancer prevention is to learn how and when to apply the agents in a non-toxic fashion at the correct stage of tumor development. Some possibilities will be discussed.

Citation Format: Martin A. “Mac” Cheever. High priority immunotherapy agents in development to treat and prevent cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN04-02.