T cell therapies are revolutionizing cancer treatment by achieving long-lasting remission in cancers, such as melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, and leukemia and lymphoma. An important function of the immune system is its ability to discern between normal cells in the body and those it sees as “foreign.” This lets the immune system attack the foreign cells, including cancer cells, while leaving the normal cells alone. To do this, it uses “checkpoints.” Immune checkpoints are molecules on certain immune cells that need to be activated (or inactivated) to start an immune response. Cancer cells sometimes develop the means to use these checkpoints to avoid being attacked by the immune system. But drugs that target these checkpoints have much promise as cancer treatments. These drugs are called checkpoint inhibitors, and first originated from the work of Prof. Dr. James Allison, Ph.D. at UC Berkeley. Dr. Allison would later be awarded the Nobel Prize in Physiology or Medicine for this work.
Importantly, checkpoint inhibition is a new paradigm in treating cancer, allowing the immune system to operate normally where T-cells can once again attack the cancer cells because of the drug therapy. Unlike previous methods, checkpoint inhibitors don’t work directly on the tumor or over boost the immune system. The checkpoint inhibitors simply institute “physiological renormalization” (Maguire, 2019), restoring normal T-cell physiology. The checkpoint inhibitor works by using a monoclonal antibody, a protein, that blocks the cancer cell signaling to the T-cell’s checkpoint mechanism. Normally the cancer cell is sending a signal to the T-cell that “fools the T-cell into thinking” that the cancer cell is a normal cell and one that should not be attacked by the T-cell. Important to the T-cells acting to kill the cancer cells, even when the patient is taking checkpoint inhibitors, is a plant based diet rich in fiber. The T-cell activity on the cancer cells is facilitated by fiber consumption, allowing the checkpoint inhibitor to work better to destroy the cancer cells (Worcester, 2019). I write about this in my new book, “Thinking And Eating For Two: The Science of Using Systems 1 and 2 Thinking to Nourish Self and Symbionts.”
While Dr. Allison’s work on T-cells began in 1985 at Berkeley, the same year I came to Berkeley and joined the same department, Molecular and Cell Biology, Prof. Dr. Jennifer Doudna, Ph.D. at UC Berkeley would begin work in about 2010 on a technology as revolutionary as that of Dr. Allison. As co-inventor of CRISPR-cas9 technology, along with Prof. Dr. Emmanuelle Charpentier, Ph.D of the Max Planck Institute in Germany, Dr. Doudna invented a technology that would allow cells to be engineered by editing their DNA. Using this methodology, T-cells can now be made to inherently avoid the cancer cell’s evasion mechanisms using their ability to activate the checkpoint in T-cells to stop the T-cell from attacking the cancer. Using the CRISPR-cas9 methodology, the T cell receptor (TCR) complex located on the surface of T cells, which is central for initiating successful anti-tumor responses by recognizing foreign antigens/peptides bound to MHC-molecules, the patient’s own T cells are genetically engineered to express a synthetic (transgenic) TCR that can specifically detect and kill tumor cells. CRISPR-cas9 engineered T cell therapies are just beginning to revolutionize cancer treatment by achieving long-lasting remission in blood-related cancers, such as leukemia and lymphoma. These therapies involve removal of patient T cells, “reprogramming” them to attack cancer cells, and then transferring them back into the patient. Targeted gene inactivation (knockout) using CRISPR-Cas9 can enhance T cell activity and has the potential to expand cell therapy applications (Hamilton and Doudna, 2020).
Until the study of Stadtmauer et al (2020), whether CRISPR-Cas9–edited T cells would be tolerated and thrive once reinfused into a human was unknown. Stadtmauer et al (2020) present data from a phase 1 clinical trial (designed to test safety and feasibility, but not efficacy) on the first three cancer patients treated with CRISPR-Cas9–modified T cells. Given one infusion of the engineered T-cells, the three patients did not experience the feared “cytokine storm” that patients have previously experienced in clinical trials using genetically altered cells. The authors found a high-level engraftment and long-term persistence of the infused CRISPR-Cas9 engineered T cells in one of the patients who was carefully analyzed 4 months after infusion. The procedure uses lymphodepleting chemotherapy, and therefore the negative side-effects associated with this procedure were observed. Although only three patients were treated, these findings represent an important advance in the therapeutic application of gene editing and highlight the potential to accelerate development of cell-based therapies, however experience with more patients given infusions of CRISPR-engineered T cells with higher editing efficiencies, and longer observation after infusion, will be required to fully assess the safety of this approach.
Hamilton and Doudna (2020) Knocking out barriers to engineered cell activity. Science, DOI: 10.1126/science.aba9844.
Maguire G (2019) Physiological renormalization using systems therapeutics. Future Sci OA. 2020 Jan; 6(1): FSO428.
Sanders R (2018) UC Berkeley research led to Nobel Prize-winning immunotherapy. Berkeley News, Oct.1, 2018.
Staudtmauer EA et al (2020) CRISPR-engineered T cells in patients with refractory cancer. Science, DOI: 10.1126/science.aba7365
Worcester (2019) Diet appears to play an important role in response to anti-PD-1 cancer immunotherapy. MD Edge, March 1, 2019.