Over the previous two articles, I explained how different types of immunotherapies target and kill cancers. While a variety of these therapies utilize the homing proteins, antibodies, and antigen receptors our bodies create naturally, they use different mechanisms to target and eliminate cancer. Some of these therapies are created entirely in laboratories and administered widely to patients. Adoptive cell therapies, on the other hand, utilize cells from our own bodies which allow for highly specialized treatments in each individual. This article will break down a recent publication describing the successful treatment of an otherwise untreatable metastatic breast cancer using a form of adoptive cell therapy.
In my previous article, CAR T Cell Therapy: Engineering the Immune System to Fight Cancer, I outlined some of the roadblocks to treating solid tumors like breast cancer with adoptive cell therapies such as CAR T cell therapy. In these cancers, the microenvironment around the tumor is often harsh, precluding the survival of the immune cells that attempt to attack the tumor. As I delineated in Immunotherapy: Harnessing the Power of Our Own Cells to Treat Cancer, however, there is evidence that our own immune cells try to fight off cancer on their own. Many breast cancer tumors, in fact, contain immune cells called tumor infiltrating lymphocytes (TILs). Studies have also shown that the presence of these TILs often correlate with better prognoses and responses to treatments. These connections indicate that our immune cells can fight off cancer — they just need some help.
Many clinical trials are currently underway investigating the efficacy of different adoptive cell therapies on solid tumors. One current trial at the National Cancer Institute is examining how TILs can help treat metastatic cancers. The remarkable results from the treatment of one trial participant who had ER+ HER2- metastatic breast cancer unresponsive to chemotherapy were published in the June, 2018, issue of Nature. This study utilized mechanisms similar to those used in cancer vaccines I discussed in Immunotherapy: Harnessing the Power of Our Own Cells to Treat Cancer. Like cancer vaccines, this TIL adoptive cell therapy harnesses the power and specificity of a patient’s own immune cells, called T cells, and targets them against cancer cell-specific protein markers, called antigens.
In contrast to cancer vaccines, however, the TIL adoptive cell therapy used in this trial is hyper-specific to each patient. Rather than target common antigens among all trial participants, the scientists identified genes that had mutations in the cancer cells by analyzing DNA from the tumors in each patient. This allowed the scientists to select antigen targets present in the cancer cells but not in the non-cancerous cells. DNA sequencing of the 49-year-old female patient presented in this study revealed 69 DNA mutations that were predicted to change the sequence of their corresponding proteins.
The scientists not only utilized the tumor samples to analyze DNA from the patient, they also isolated the TILs — in this case, specifically T cells. As you may recall, T cells contain a specialized antigen receptor that can only identify certain proteins, causing them to only detect cells that express that protein. While cancer vaccines such as sipuleucel-T train T cells to identify certain proteins through their antigen receptors, T cells that have infiltrated tumors already contain specialized antigen receptors. In this study, the scientists took advantage of these "pre-trained" T cells and selected those that detected proteins specific to cancer cells. Combining the information from the DNA mutations in the cancer cells, the researchers determined which proteins differed between cancerous and non-cancerous cells, and whether the TILs from the tumor could detect these proteins. They identified four genes containing mutations in the cancer cells, for which there were pre-trained T cells from the tumor that detected the resulting mutant proteins.
In order to fight the cancer, the scientists enhanced the response of these pre-trained T cells by stimulating the growth of these cells in the laboratory. As you may recall, T cells are activated by other immune cells that present fragments of the target antigens. In order to expand the pool of T cells, the scientists fed fragments of the target antigens identified from the DNA sequencing to these immune cells called dendritic cells. Once the dendritic cells and the pre-trained T cells were mixed together, the T cells became activated and divided. The large pool of pre-trained T cells was then infused back into the patient.
Once the cells were back in the bloodstream of the patient, they were able to seek out the cancer cells throughout the body. T cells can perform a variety of immune functions, from attacking and killing target cells directly to stimulate other immune mechanisms. Infusing cells that have such vast capabilities therefore allows multiple types of immune responses to be mounted against the cancer cells. The levels of the T cells were tracked over time after infusion in the patient. Six weeks after the cell transfer, the tumor burden had been reduced by 50% and 22-months after treatment there was no more detectable cancer. The scientists, however, were able to detect the T cells specific to these tumor antigens up to 17 months after infusion.
Versions of adoptive cell therapies have been used for decades. As technology advances, however, these therapies have become even more personalized, which not only lowers the risk for rejection or adverse immune responses against donor tissues but also increases the specificity of the treatment. In this study, the use of DNA sequencing allowed scientists to identify the specific genes to be targeted in the patient and to specifically use the patient’s cells that identified these mutated proteins. This same analysis in another patient likely would have yielded different targets.
One remarkable outcome of this study was that it showed that hormone-driven cancers previously not amenable to adoptive cell therapy were able to be successfully treated through this method. While adoptive cell therapy using TILs had been a well-established for the treatment of cancers that had high levels of mutations, breast, ovarian, and prostate cancers generally have fewer DNA mutations, which decreases the chances that TILs will be able to successfully target the cancer cells. The treatment in the current study, however, successfully eliminated the cancer by targeting only four mutated proteins unique to the cancer.
In this study, TIL adoptive cell therapy successfully treated ER+ HER2- metastatic breast cancer that had previously been unresponsive to chemotherapy. While many breast cancer immunotherapies target the HER2 protein, those treatments were not an option for this case due to the lack of expression of HER2. Thus, the highly specialized TIL adoptive cell therapy gave hope for a treatment to a cancer that had few, if any, treatment options. Scientists used information from one of the cancer lesions to identify four mutant proteins that the patient’s immune response had already attempted to attack. They then boosted the natural immune response by growing more of these pre-trained T cells in the laboratory and then infusing them back into the patient’s body. The success of TIL adoptive cell therapy in this cancer gives hope for the treatment of other hormone-driven solid tumor cancers.
The highly specialized nature of adoptive cell therapies like the TIL therapy discussed here, as well as cancer vaccines and CAR T cell therapies I discussed over the past few articles, are one aspect of the recent trend in precision medicine. While I previously examined how understanding the landscape of genetic mutations in a cancer helps guide both diagnostics and choice of treatments, these personalized immunotherapies utilize mutations as targets of treatment. Furthermore, TIL adoptive cell therapy enhances the power of the natural immune response by selecting the immune cells that will be most effective at eliminating the cancer. The advances in technology that make personalized adoptive cell therapies possible are enabling us to learn more about our immune responses and how to manipulate them to target cancer cells. As every cancer is unique, these astonishing and promising therapies, together, may make it possible to one day treat all cancers that were once considered untreatable.