# Novel therapeutic approaches for enhancing anti-tumor immunity in SCLC

> **NIH NIH U01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $702,580

## Abstract

PROJECT SUMMARY
Small cell lung cancer (SCLC) is a highly lethal malignancy for which new therapeutic strategies are
desperately needed. One promising avenue is the use of immunotherapy (IMT) agents such as PD-1/PD-L1
pathway inhibitors. Despite its high mutation burden, however, data from our group and others indicate that
SCLC paradoxically has an immunosuppressed phenotype with relatively low levels of infiltrating T-cells,
reduced antigen presentation, and increased levels of CD47, a suppressor of myeloid function. Furthermore,
initial clinical testing suggests that most SCLC tumors often express low or very low levels of PD-L1 and fail to
respond to PD-1 inhibitor monotherapy; IMT resistance also inevitably emerges in responding tumors by
mechanisms that have not yet been characterized. Thus, immunosuppressive mechanisms other than the PD-
1/PD-L1 pathway are likely to play a major role in SCLC, and novel therapeutic approaches and combination
therapies are needed to realize the potential of IMT in SCLC.
The goal of this proposal is to address this issue by identifying new IMT targets and novel combination
regimens, and to rapidly translate them into the clinic. Our team already has promising leads. First, we
identified that SCLC is highly vulnerable to drugs targeting DNA damage repair (DDR) including PARP and
Chk1 inhibitors, a finding now supported by early clinical results. Our preliminary data further suggest that DDR
inhibition may increase PD-L1 expression and, by increasing the production of tumor-associated neoantigens
(TAA), may sensitize tumors to IMT. In Aim 1, we will test whether DDR inhibitors can increase the expression
of TAAs, and enhance the efficacy of PD-1/PD-L1 inhibitors. Second, we have developed a novel strategy for
protecting immune cells from the cytotoxic effects of chemotherapy by using inhibitors of CDK4/6, which can
be used to protect immune cells, but not RB-deficient SCLC cells. In Aim 2, we will test whether CDK4/6
inhibition can enhance the anti-tumor effects of immune cells by protecting them from chemotherapy-induced
cytotoxicity and enable improved chemotherapy/IMT combinations in SCLC. Third, we have identified the
“don't-eat-me” signal CD47 as a novel IMT target for SCLC; blockade of CD47 effectively promotes the
phagocytosis of SCLC cells by macrophages and inhibits tumor growth. In Aim 3, we will test whether targeting
this CD47 myeloid checkpoint can enhance antitumor immunity and the efficacy of PD-1/PD-L1 blockade and
chemotherapy in vivo in SCLC models.
The overall hypothesis tested here is that antitumor immunity can be enhanced in SCLC by targeting all these
processes, leading to more effective IMT combination regimens. These studies will be facilitated by novel
immune-competent pre-clinical murine SCLC models that we have developed and by a multidisciplinary team
including clinical and laboratory investigators, immunologists, pathologists, and others with a record of
innovation in SCLC and IMT...

## Key facts

- **NIH application ID:** 9974992
- **Project number:** 5U01CA213273-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Lauren Averett Byers
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $702,580
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974992

## Citation

> US National Institutes of Health, RePORTER application 9974992, Novel therapeutic approaches for enhancing anti-tumor immunity in SCLC (5U01CA213273-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974992. Licensed CC0.

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