Checkpoint modulators such as PD-1 and PDL-1 inhibitors have changed the face of cancer care, eliciting long-lasting responses in select patients with solid tumors that have metastasized. Although a few patients receive great benefit, there is some frustration in the field that these new immunotherapies do not as yet help more patients.
“Checkpoint modulators in lung cancer have had spectacular results in a few cases and responses in about 20 percent of patients but have done little in the other 80 percent,” says John M. Wrangle, M.D., an MUSC Health medical oncologist who specializes in immunotherapeutic approaches to cancer, especially lung cancer. “That is disappointing clinically. We want immunotherapy to work for more people.”
Combining checkpoint modulators with other immunotherapeutic strategies will likely be necessary if more lung cancer patients are to benefit. Wrangle and his collaborators, which include cancer immunologists Mark P. Rubinstein, Ph.D., and Chrystal M. Paulos, Ph.D., thoracic surgeon Chadrick E. Denlinger, M.D., and bioinformatician Jeff Hammerbacher, are currently working on two related strategies that lie at the interface of immunotherapy and genetics.
The first and most immediate goal of the team is to create a tumor-infiltrating T lymphocyte (TIL) product for lung cancer that they hope to bring to clinical trial at MUSC Hollings Cancer Center. In TIL therapy, a type of adoptive cell transfer (ACT) therapy, T cells are harvested from a patient’s tumor, expanded outside the body and reinfused into the patient to enhance the immune response against cancer. The availability of an FDA-registered clean room suite in the MUSC Center for Cellular Therapy, where cells harvested from the patient can be expanded and manipulated safely before reinfusion, makes a trial of TIL therapy feasible at Hollings.
“The Center for Cellular Therapy is one of the few GMP- and FACT-accredited facilities in the country that is able to move a trial such as that for TILs to clinic with efficiency and safety,” says MUSC Health transplant surgeon Satish N. Nadig, M.D., Ph.D., medical director of the center. Shikhar Mehrotra, Ph.D., is the center’s co-scientific director for oncology and immunotherapy programs.
The second goal of the team is to identify neoantigens that are relevant to lung cancer and can be used to fine tune their TIL product and, in the longer term, to create custom personalized vaccines that can be given in combination with other immunotherapies to improve outcomes for patients with lung cancer.
Developing TIL therapy for lung cancer
Approval of chimeric antigen receptor (CAR) therapy, a type of ACT, by the FDA in August 2017 for pediatric acute lymphoblastic leukemia (see story on page 8) has helped ignite enthusiasm about ACT’s clinical potential. While the FDA-approved CARs are genetically engineered to target CD19, which is expressed on both healthy and cancerous B cells, TILs are naturally occurring and target the tumor only. “TILs are already within you, and that is one reason they are so good,” says Paulos, whose laboratory is growing TILs from patients with lung cancer and other solid tumors, including melanoma and breast cancer. “They are natural and fine-tuned to elicit a specific immune response against a mutated tumor.”
Steven A. Rosenberg, M.D., Ph.D., at the National Cancer Institute and others have achieved impressive clinical responses in a substantial subset of patients with metastatic melanoma. A few patients have had such long-lasting responses that they are likely cured. In a pooled analysis of recent clinical trial protocols, the overall response rates and complete response rates for metastatic melanoma were around 50 percent and 20 percent, respectively, with 95 percent of those with complete responses remaining disease free for at least five years.1
In 2017, Wrangle, Rubinstein and Paulos traveled to M.D. Anderson, a leader in TIL therapy, to learn its protocols for expansion and reinfusion of TILs. They then sought out Denlinger, who has been providing them with lung tumor tissue removed during surgery. “We are taking lung cancer specimens and preserving them fresh and sending them straight to the laboratory with the intent of growing out the T cells,” says Denlinger. They have now isolated TILs from about two dozen tumors and have successfully navigated the methodological and logistical challenges of expanding them in the laboratory. Although their initial focus has been on lung tumors, they are also working on isolating and expanding TILs from metastatic tumors in the liver, provided by Nadig, and in the brain, provided by resident neurosurgeon Fraser C. Henderson Jr., M.D., via the Hollings Cancer Center Tissue Biorepository.
The next steps are to implement the protocols optimized in the laboratory at the Center for Cellular Therapy, to complete an investigational new drug application and to find funding for the trial.
The role of neoantigens
Realizing that alternative approaches are likely to be necessary, the MUSC team is also working at the interface of immunotherapy and genetics to help fine tune TIL therapy and to develop custom, personalized vaccines that could one day be administered in combination regimens to expand the number of people with lung cancer who benefit. Next-generation genomic sequencing of both healthy and cancerous tissues has enabled identification of cancer-associated mutations known as neoantigens. Because these neoantigens result from mutations that are unique to cancer cells, immunotherapies targeting them should not in principle damage normal tissue. Cancer, which develops due to mutations, could in fact be made recognizable — and precisely targetable — by the immune system as a result of some of those very mutations. Ironically, the mutations that define cancer and make it such a fearsome foe could become its Achilles heel.
Fine-tuning TIL therapy
TILs have historically shown efficacy in metastatic melanoma, a cancer with a high mutational load and one that has responded well to a variety of immune-based therapies. Because lung cancer has almost as high a mutational load as melanoma and has recently been shown to respond to checkpoint therapy, the MUSC team thinks that TIL therapy could also offer benefit to patients with lung cancer.
Relying on the Center for Genomic Medicine directed by Stephen P. Ethier, Ph.D., the MUSC team is having each of the tumor samples sequenced so that neoantigens can be identified. Sophisticated machine learning and other advances in bioinformatics have enabled predictive algorithms to be developed to identify which of these neoantigens are most likely to trigger an immune response. The MUSC team is using a predictive algorithm that is being optimized by Hammerbacher, who holds faculty positions at both MUSC and Mount Sinai and was formerly a data manager for Facebook, to identify the neoantigens most likely to provoke an anti-cancer immune response.
“Out of the tens of thousands of mutations a tumor may harbor, maybe only a handful interact with the immune system,” says Wrangle. “The purpose of the algorithm is to separate the wheat from the chaff.”
It is hoped that one day the team could use that information to identify TILs that target the most immunoreactive neoantigens. “When we identify a neoantigen, we can match a certain T cell with a certain antigen and that becomes the finely tuned TIL product that we give back to the patient,” says Denlinger.
However, it is also possible that the appropriate T cells could be found in the blood, pointing the way forward for a much less logistically challenging form of ACT — one which requires a simple blood draw instead of surgery to obtain tumor tissue.
An alternative strategy would be to develop customized vaccines tailored to the neoantigenic profile of a patient’s cancer. Such a vaccine could consist of a mutated protein or peptide (i.e., the neoantigen) administered with an adjuvant to optimize the immune response. “If less than one percent of T cells in the blood of a patient are tumor-reactive, and we can use a vaccine to activate and expand these cells to over 20 to 30 percent in circulation, that might have dramatic therapeutic value, particularly when such a vaccine is combined with other newer therapies,” says Rubinstein.
Many pharmaceutical companies — both long-established ones and startups —are conducting clinical trials of these customized vaccines, both as monotherapies and in combination with other treatment approaches such as checkpoint modulators, radiotherapy and chemotherapy. These trials are in their infancy, with very little actual clinical data reported. The very nature of these vaccines challenges the usual pathway to regulatory approval. Because they are customized to the patient, there is no “one” product that can be tested in clinical trial. The efficacy of the treatment may need to be judged in part on the sensitivity and accuracy of the predictive algorithm itself.
“If you’ve got a typical FDA-approved drug, it’s been tested in a thousand people and has been given in exactly the same manner to everyone,” says Wrangle. “With a custom vaccine, if it is based on a predictive algorithm, that algorithm is the thing that is critical for the ultimate efficacy of the therapy.”
Wrangle is confident in the predictive algorithm being optimized by Hammerbacher and in the ability of his team to compete in this new pharmaceutical space.
“How will we compete with companies worth hundreds of millions of dollars?” asks Wrangle. “It’s through innovation in terms of the vaccination strategy. That’s where basic science is indispensable. If existing groups had it right already, we would have heard about it.”
The MUSC team is working hard to get it right. They are seeking answers to fundamental questions, such as the number of neoantigens needed for an effective vaccine and the proper adjuvants to use with it to increase immune response, and are refining the manufacturing process for proteins and the software they will need to interpret their results.
“We don’t think custom vaccines will do it by themselves,” says Wrangle. “So it is important to do preclinical work to understand how you fully engender or accomplish an effective immune response and how we can best optimize our vaccine strategies.”
1 Rosenberg SA, et al. Clin Cancer Res. 2011;17:4550–4557.
2 Hinrichs CS and Rosenberg SA. Immunol Rev. 2014 Jan;257(1): 56-71.