A new approach to cancer treatment
Like injured boxers, potentially life-saving elements of the human immune system lie buried within a cancerous tumor unable to land a knock-out blow.
The tumor may wall-off or incapacitate these key immune killer cells, called tumor infiltrating lymphocytes (TILs), effectively blocking their main function: the destruction of cancer cells.
But, what if it were possible to rehabilitate the TILs? What if scientists had a way to awaken them, put them back into the tumor and create a resurgent mass of cells capable of knocking out the cancer? And what if clinicians could then deliver a blueprint in the form of a vaccine that would trigger the patient’s own immune system into creating even more anti-cancer cells that would not only help kill the tumor, but prevent the cancer from ever coming back?
While simple in theory, previous attempts to do so came up short. But now there are three punches that TGen investigators are throwing in a promising new effort that could theoretically disable virtually all cancers.
TGen’s approach takes precision genomics, led by Jeffrey Trent, Ph.D., TGen’s Research Director, and identifies the patient’s genetic changes within their actual tumor cells. That is combined with precision immunotherapy, led by John Altin, Ph.D., a TGen Assistant Professor specializing in immune-therapy, identifying which among hundreds of genetic changes can be found on a patients cells. The final blow, led by Dr. Sunil Sharma, M.D., TGen’s Physician-In-Chief, is “educating” and then returning the cells to the patient to recognize targets and have their own TILs search out and kill their tumor cells.
“Until recently, the field has lacked the molecular specificity required to re-educate the T cells,” says Dr. Trent, whose lab is actively involved in the genomic underpinnings of the process. “Dr. Altin’s work at TGen has developed an approach that identifies the exact tumor targets that the T cells need to see on the tumor. This allows Dr. Sharma’s team — in concert with City of Hope’s clinical cell processing team — to properly ’re-educate’ and expand the TILs so they can do their job and kill the tumor.”
In the coming months, the TGen team will conduct a clinical trial on as many as 60 patients with varying types of cancer to determine the safety and effectiveness of this unique treatment method.
“We’re attempting to fuse TIL technology with precision vaccines to achieve a positive treatment response,” said Dr. Sharma, “This innovation, if successful, will take cancer care to an entirely new level.”
Dr. Altin agrees, adding that laboratory experiments have already shown that the concepts should work in multiple cancer types: “The approach we are developing could be applied to almost any tumor in the human body.”
Snap: the first treatment
The treatment method requires a four-step process.
First, through a biopsy, clinicians extract cells from a patient’s tumor, including TILs. Scientists perform deep DNA and RNA sequencing to understand changes unique to the patients’ cancer, and then sort these cells in the laboratory. Second, the TILs undergo rigorous genomic and proteomic analysis to identify those that have the greatest potential to be effective against the tumor. Third, the chosen TILs are isolated, multiplied and retrained to identify and attack specific antigen peptides (proteins) on the surface of a patient’s cancer cells. The retrained TILs — composed primarily of immune system T cells — are known as specific neo-antigen peptide TILs, or snapTILs™. The fourth step involves introducing the snapTILs back to the patient through intravenous infusion.
“What’s most fascinating is that we leverage each patient’s genomic profile and a handful of the right T cells to drive the process,” said Dr. Sharma. “Because we can replicate the most effective cells in the laboratory environment, we’re capable of making millions to help each patient. It’s a very genomic and immunologically precise way of aligning the cells against the tumor.”
The process repeats itself with each patient, because each patient’s cancer cells are different — even within the same type of cancer, and even that type of cancer within each patient. It’s a penultimate example of precision medicine.
Dr. Altin calls this therapeutic a “living drug.”
“Most drugs involve giving some chemical, something that is not alive, to the patient,” he explained. “Whereas, in cellular therapy, you are actually taking living cells, re-training them, and putting them back into the patient.”
Vaccine: the second treatment
Developing a vaccine to fight cancer is the Holy Grail of oncology. But is it possible?
Past attempts have simply lacked the precision needed to sufficiently activate the body’s own innate immune system to identify and thwart tumor cells in the earliest stage of development, prior to their taking root.
As with the snapTIL treatment, TGen’s vaccine relies on cells extracted from the tumor. Following identification and isolation of antigens on the surface of cancer cells they’re infused in the patient where, once again, the body’s immune system recognizes them and mounts a response. This stimulates the T cells already present in the patient, causing them to multiply and, like those created in a laboratory, incapacitate the tumors.
“The vaccine eliminates the need to replicate the effective cells in the laboratory by prompting the body’s own immune system to provide the same function,” said Dr. Altin.
Unlike the single-use snapTIL treatment, a patient could theoretically receive the vaccine multiple times in order to stimulate, or re-stimulate, the immune system against the cancer.
TGen will begin recruiting patients for the clinical trial phase in the near future. Ideally, said Dr. Sharma, they would like to have 60 patients representing a variety of tumor types: 30 to test the snapTILs treatment; and 30 to test the vaccine. Eventually, patients would receive both in tandem.
Different from CAR T therapy
Dr. Sharma is quick to point out that while similar in nature, both snapTIL and the vaccine differ from the more well-known CAR T therapy.
A drawback of CAR T therapy is that they’ve proven effective only in blood cancers such as lymphomas, multiple myeloma and certain types of leukemia. They have yet to show effectiveness against more genetically complex solid tumors, such as lung, breast, colon or pancreatic cancers.
“I believe an advantage our approach holds over CAR T is that we are training T cells for a specific function rather that attempting to engineer a cell to perform a certain task,” explained Dr. Sharma.
Potential for mRNA in cancer treatment
The COVID-19 vaccines made by Pfizer and Moderna rely on a newly refined technology nearly three decades in the making called mRNA. Compared to previous vaccines, mRNA based vaccines are highly potent, safe to administer and rapidly developed at relatively low costs.
Dr. Altin said TGen researchers are not yet pursuing mRNA technology for cancer vaccines, but are considering it for future projects: “It’s definitely got us thinking about whether we can use that mRNA platform.”
Instead of a vaccine that gives patients versions of their own antigen peptides, they would receive mRNA, which is the genetic code that refers to those peptides.
“In the same way that the COVID vaccines work, those cancer peptides would be made by the body itself. The vaccine would provide the mRNA instructions to the body, which would then make the antigens,” Dr. Altin said. “Using mRNA would elevate anti-cancer vaccines to a whole new level.”
For now, though, snapTILs and vaccines are providing a sufficient enough challenge and one, that if successful, could potentially eliminate the need for additional therapies.
