“Immunotherapy may not be a single silver bullet, but we may need several therapies in combination or one after the other to maximize its efficacy. We also need to develop better pre-treatment tests to find which patients are most likely to benefit, and avoid side effects in patients who are not likely to benefit.”
- Michael Sabel, MD, ASCO Expert
The key lesson that is emerging is that the mechanism of resistance to immunotherapy will be unique in each patient. The immune response to cancer is shaped by the molecular characteristics of the tumor, the immune profile of the tissue surrounding the tumor (microenvironment), and patient-specific factors, including their genome and even the composition of microbes in their gut or mouth. Moreover, the immune response is continuously evolving during the course of the disease and can be either enhanced or dampened as a result of various cancer treatments.1
Researchers have proposed that comprehensive “tests” for immunotherapy susceptibility or resistance include the following: general immune status, analysis of the tumor genome, immune checkpoint molecules on the tumor surface, immune cells and immunosuppressive molecules in the tumor microenvironment, and features of the microbiome in their body.
Such an assessment would inform choice of treatment, tailored to the specific biologic underpinnings of the resistance. For tumors that are invisible to the immune system due to lack of “foreign” antigens on their surface, chemotherapy and other treatments that destroy cancer cells can help build an anti-tumor immune response, as dying cancer cells release antigens the immune system reacts to. Cancer vaccines can also be helpful in this scenario.
If the problem is insufficient T-cell activation in lymph nodes, it may be helpful to block multiple immune checkpoints and/or activate immune stimulatory pathways (e.g, by blocking 4-1BB, OX40, ICOS).4 Once activated, tumor-specific T cells rely on chemical signals to find and reach the tumor site, but some tumors suppress these signals. Early research suggests that VEGF inhibitors, cytokines, and adoptively transferred T cells (patient’s own immune cells genetically reprogrammed in the lab and injected back into the patient) may help remedy this this deficit.
Finally, to counter tumor’s suppression of immune responses, one might try blocking multiple immune checkpoints, activating immune stimulatory pathways, or depleting immunosuppressive cells. Reducing tumor size through surgery or other therapy prior to starting immunotherapy can be helpful when the tumor is too large for the immune system to clear.4
A broad range of treatment approaches to enhance the efficacy of immunotherapy are already being tested in clinical trials1:
- Different checkpoint inhibitors combined (targeting PD-1/PD-L1, CTLA4, TIM 3, or LAG 3)
- Checkpoint inhibitors plus
- immune stimulation (with anti-41BB, anti-OX40 antibodies)
- metabolic modulators (e.g., inhibitors of TGF-beta, CXCR4, CCR4)
- macrophage inhibitors
- oncolytic viruses
- cancer vaccines
- adoptive immune cell transfer (e.g., CAR T cells)
- targeted therapies (e.g., VEGF, BRAF, MEK, EGFR, PARP, PI3K delta, mTOR, RAF, and glutaminase inhibitors)
- radiation therapy
- epigenetic drugs
- natural killer cell activation
Any of these approaches could help restore a robust immune response to cancer. As much as a single immunotherapy drug can work against many different cancer types, perhaps ironically, there is no universal antidote to immunotherapy resistance.
In the future, the choice and timing of a treatment for immunotherapy resistance will ideally be personalized and tailored to the root causes of resistance in each patient – but we are not at that point yet.
“We will see many more clinical trials designed not only to learn whether a drug works, but also to learn more about why it may not work in certain patients. Patient participation in clinical trials is paramount to answering some of these questions,” said Dr. Sabel.
Read Part I of this series to learn how resistance to immunotherapy happens.
1. Sharma P, Hu-Lieskovan S, Wargo JA, et al: Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 168:707-723, 2017
2. Marabelle A, Aspeslagh S, Postel-Vinay S, et al: JAK Mutations as Escape Mechanisms to Anti-PD-1 Therapy. Cancer Discov 7:128-130, 2017
3. Beatty GL, Gladney WL: Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 21:687-92, 2015
4. Baumeister SH, Freeman GJ, Dranoff G, et al: Coinhibitory Pathways in Immunotherapy for Cancer. Annu Rev Immunol 34:539-73, 2016