Focus: Solid Tumors

Chimeric antigen receptor (CAR) T cells benefit patients with treatment resistant B-cell leukemia, B-cell lymphoma and multiple myeloma, raising hopes that CAR T cells could be used to treat “solid” cancers, including breast cancer, lung cancer, pancreatic cancer, brain cancer, and sarcomas. Studies show that CAR T cells can work against solid cancers in mouse models, but they also reveal challenges that must be overcome for treating human patients. 

One major challenge relates to the fact that the protein targets that CAR T cells recognize in leukemia/lymphoma/myeloma are not expressed on vital normal tissues, whereas CAR T-cell targets for solid cancers are generally expressed on vital tissues as well, albeit at lower levels. Therefore, CAR T cells targeting solid cancers pose greater risk to harming normal tissue.

A related challenge relates to greater suppression and evasion of immune responses by solid cancers, which requires more potent CAR T cells. These competing issues (“increased risk for toxicity combined with a need for greater potency”) have led to limited progress for solid tumors.

The Mackall lab recently developed a new CAR T-cell platform that both increases potency AND increases safety. 

SNIP-CARs allow “remote control” of CAR T cells using a drug administered as a pill. SNIP-CARs contain a molecule (called a protease) that continuously “snips” the CAR molecule in half, preventing its function unless a drug is present to inhibit the “snipping protease.” Drugs that inhibit the protease are FDA-approved and well-tolerated. SNIP-CARs are “OFF” at baseline but are able to be activated (they still require the tumor target to be activated) in the presence of the drug.

In mouse models where standard CAR T cells killed the animals due to toxicity, stopping the drug after the animals became ill allowed complete recovery. Surprisingly, in settings where toxicity was not an issue, SNIP-CARs plus daily dosing of the drug resulted in greater tumor control than seen with standard CAR T cells. This is due to the variations in drug levels by drug metabolism, which provided the CAR T cells with periods of activation followed by periods of “rest.” Finally, in situations where tumor and normal vital tissue shared the target and standard CAR T cells killed the animals, a lower dose of the drug allowed the SNIP-CAR T cells to attack the tumor but ignore the normal tissue. 

This proposal generates the necessary processes, procedures and materials needed to test SNIP-CARs in patients with solid cancers whose solid cancers are not effectively treated with standard therapies. The proposal will amplify ACGT investment by leveraging substantial infrastructure in place at Stanford University to greatly accelerate clinical testing of a cutting-edge cancer gene therapy platform for patients with critical unmet need.

Cancer immunotherapy is revolutionizing the treatment of many cancers. This revolution is being led by drugs that enhance the immune system’s T cell’s ability to kill cancer cells. This includes drugs such as Keytruda, an antibody that blocks a molecule called PD1 on T cells, and Kymriah, a living drug which is a product of using gene therapy to engineer a patient’s own T cells to better attack their cancer cells. Despite the amazing successes in some patients, unfortunately, not all patients respond to current immunotherapies.  

One of the cell types that appears to be responsible for the failure is a cell type called a macrophage. Macrophages are part of the immune system and have a function in protecting us from infections. However, tumors can reprogram macrophages to suppress other cells of the immune system, which benefits the tumor by preventing killer immune cells from entering the tumor and killing the cancer cells. Considerable evidence indicates that eliminating the macrophages of a tumor could improve patient outcomes and response to treatments, but traditional pharmacological approaches for doing this have not shown clinical benefit.  

To overcome the limitations of traditional drugs, we will harness the power of gene therapy and develop a new type of living drug in which we would gene engineer a patient’s own T cells to kill the immune suppressing macrophages in their tumors. This would eliminate a major barrier to immunotherapy treatment and help the patient’s immune system to eliminate cancer cells. This novel strategy will draw on the considerable advances in the gene therapy field that led to the development of Kymriah, and other drugs based on the use of chimeric antigen receptor (CAR).  

We will develop a CAR that specifically kills macrophages in a tumor, while sparing macrophages in healthy tissue. We will test our strategy in preclinical animal models of lung and breast cancer to determine if our tumor macrophage killing CAR can lead to the elimination of aggressive tumors. We will also evaluate further refinements to the therapy to make these CAR even more potent at helping the immune system permanently eliminate different cancer. This project will lead to the development of a new gene and cell immunotherapy with the potential to treat a wide variety of cancers and help a patient’s own immune system end their cancer. 

This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America. 

Few procedures are available for physicians to rapidly and reliably harness immune responses to fight cancer. For example, bioinformatics tools can predict cancer proteins that T cells could react with, but vaccines developed from them commonly fail because the immunized patients do not have enough T cells that are inherently able to recognize the predicted antigens.  

The goal of our research is to develop injectable nanoreagents that can genetically program T cell receptors (TCRs) into circulating lymphocytes, enabling them to recognize cancer proteins. Specifically, we hypothesize that customized cancer-targeting can be introduced into immune cells by combining anti-cancer vaccines with techniques that induce endogenous CD8 T cells to express TCRs specific for the vaccines, and consequently provide them with the ability to react with cancer cells. We further hypothesize that this platform can be used to program helper cells with defined “MHC class-II-restricted TCRs”, and thereby improve responses to tumor antigens compared to conventional immunization methods.  

Our multidisciplinary team of immunologists, bioengineers and geneticists has already established that injected nanoparticles can deliver engineered TCR genes into host T cells in a way that, once they are stimulated by vaccines, the lymphocytes recognize cancer antigens. Following rapid vaccine-induced expansion, these programmed cells continue to differentiate into long-lived memory T lymphocytes.  

We propose to develop a suite of nanoparticle reagents that can rapidly establish anti-cancer immunity by programming in situ specific receptors into the patient’s T cell pool. To achieve this, we will pursue the following Specific Aims:  

(1) to improve our efficiency for introducing vaccine specificity into circulating CD8+ T cells; (2) to establish that this approach boosts immune responses; and (3) to determine if our methods promote the regression of cancer regardless of the patient’s pre-existing TCR landscape.  

To assure the medical relevance of our findings, we will (i) program the lymphocytes to express an affinity-optimized receptor specific for the tumor antigen mesothelin, and (ii) use them to treat a genetically engineered mouse model that faithfully recapitulates human pancreatic ductal adenocarcinoma from inception to invasion. 

 We believe that the data, reagents, and application methods generated by our research will provide the basis for a broad repertoire of gene modification systems that can generate selective immunity against cancer and other diseases.